CN106588873B - A kind of polymorph and its preparation method and application of triaryl lupetazin ethanedisulphonate - Google Patents
A kind of polymorph and its preparation method and application of triaryl lupetazin ethanedisulphonate Download PDFInfo
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- CN106588873B CN106588873B CN201611039109.1A CN201611039109A CN106588873B CN 106588873 B CN106588873 B CN 106588873B CN 201611039109 A CN201611039109 A CN 201611039109A CN 106588873 B CN106588873 B CN 106588873B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
This application discloses (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) methyl) phenyl) and (4- methyl piperidine -1- base) ketone ethanedisulphonate three kinds of polymorphs A, B, C, totally three kinds of polymorphs and preparation method thereof and preparing the application in drug for preventing or treating mood disorder or disease related with delta opiate receptor.
Description
Technical field
The present invention relates to, but not limited to pharmaceutical technology fields, specifically, relating to, but are not limited to a kind of triaryl dimethyl
The polymorph and its preparation method and application of piperazine ethanedisulphonate.
Background technique
Depression is a kind of common mental disease, is mainly shown as depressed, and interest lowers, pessimistic, retardation of thinking,
Lack initiative, from crime, diet, sleep are poor for self-accusation, worry oneself, with various diseases, to feel whole body many places discomfort, serious person
It may occur in which suicidal thought and behavior." the Diagnostic and Statistical Manual that APA,American Psychiatric Association publishes
In of Mental Disorders " " mental disease diagnostic and statistical manual " fourth edition, depression is classified under mood disorder,
It is divided into three types: major depressive disorder, dysthymic disorder and other unspecified depression.
Cause depression factor include: inherent cause, physical factors, the function of nervus centralis media and metabolic disorder,
Mental element etc..In the effort for the treatment of depression, a variety of antidepressant compositions have been developed, for example, color Qu Lin, Fu Luoxi
Spit of fland, Paxil, Fluvoxamine, biphenylacetone.Although these drugs effectively, often generate problematic side effect, such as
Hypnosia, confusion of thinking cannot focus on and sex dysfunction.Also, there is onset time length in these drugs,
About 6 to 8 Zhou Caineng are needed to show any desired therapeutic effect.
Summary of the invention
It is the general introduction to the theme being described in detail herein below.This general introduction is not the protection model in order to limit claim
It encloses.
Present inventor has found that triaryl lupetazin compound can increase from different approaches through lot of experiments
Strong effect of the opioid recdptor in depression, and it is therefore theoretical based on opioid receptor δ-receptor, according to antidepressant activity
δ-receptor specific position develops δ-receptor agonism with following formula I structure for action target spot δ-receptor of depression
Agent triaryl lupetazin compound (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base)
(3- hydroxy phenyl) methyl) phenyl) (4- methyl piperidine -1- base) ketone ethanedisulphonate (molecular formula: C35H46FN3O8S2, molecule
And its polymorph amount: 719.88).And plan its exploitation for have effects that the new drug of antidepression and other potential effects at
Point.
Embodiment of the present invention provides (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1-
Base) (3- hydroxy phenyl) methyl) phenyl) and (4- methyl piperidine -1- base) ketone ethanedisulphonate three kinds of polymorphs, i.e. polycrystalline
Type object A, polymorph b, polymorph C；
Embodiment of the present invention additionally provides (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -
1- yl) (3- hydroxy phenyl) methyl) phenyl) and (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph A, polymorphic
The preparation method of object B, polymorph C.
Embodiment of the present invention additionally provides (4- ((R)-((2S, 5R) -4- as described in any embodiment of the present invention
(3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) methyl) phenyl) (4- methyl piperidine -1- base) ketone second
The polymorph A of disulfonate, polymorph b, polymorph C preparation method made from polymorph.
Embodiment of the present invention is additionally provided comprising (4- ((R)-((2S, 5R) -4- described in any embodiment of the present invention
(3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) methyl) phenyl) (4- methyl piperidine -1- base) ketone second
The pharmaceutical composition of at least one of the polymorph A of disulfonate, polymorph b, polymorph C.
Embodiment of the present invention additionally provides (4- ((R)-((2S, 5R) -4- (3- described in any embodiment of the present invention
Luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) methyl) phenyl) (4- methyl piperidine -1- base) ketone second two
The purposes of the polymorph A of sulfonate, polymorph b, polymorph C.
Embodiment of the present invention provides (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1-
Base) (3- hydroxy phenyl) methyl) phenyl) and (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph A, the polycrystalline
The X-ray powder diffraction figure of type object A includes the following diffraction maximum at 2 θ values: 12.1 ± 0.2 °, 19.0 ± 0.2 °, 16.8 ±
0.2 °, 18.2 ± 0.2 ° and 20.3 ± 0.2 °.
In one embodiment, the X-ray powder diffraction figure of the polymorph A further includes at selected from the following
Diffraction maximum at one or more 2 θ values of anticipating: 19.5 ± 0.2 °, 12.9 ± 0.2 °, 17.6 ± 0.2 °, 4.9 ± 0.2 °, 16.2
± 0.2 °, 8.8 ± 0.2 °, 7.3 ± 0.2 ° and 9.7 ± 0.2 °.
In one embodiment, the polymorph A is using the fusing point of differential scanning calorimetry measurement at 174.5 DEG C
To within the scope of 185.6 DEG C, optionally, about 185.6 DEG C.
In some embodiments, the polymorph A has attached XRPD shown in FIG. 1 figure and attached shown in Fig. 2
TGA and DSC figure.
To (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) first
Base) phenyl) organic solvent is added in (4- methyl piperidine -1- base) ketone, ethionic acid is then added, stirring is until no longer wash out
Solid filters, dry, obtains the polymorph A.
The solvent is selected from the group being made up of: acetone, methyl iso-butyl ketone (MIBK), methyl isopropyl ketone, hexamethylene, methyl ring
Hexane, n-hexane, petroleum ether, ether, methyl tertiary butyl ether(MTBE), 1,4- dioxane, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), first
In base pyrrolidones any one or more or tetrahydrofuran, acetonitrile, dimethylformamide, diethyl acetamide, formyl
Amine, methylene chloride, in dimethyl sulfoxide any one or more, the mixed solvent or dimethyl formyl of dimethyl sulfoxide and water
The mixed solvent of amine and water.
In one embodiment, relative to (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- bis- described in 2g
Methylpiperazine-1-yl) (3- hydroxy phenyl) methyl) phenyl) (4- methyl piperidine -1- base) ketone, the organic solvent being added
Amount is 15mL to 450mL, is optionally 15mL to 150mL, and the amount for the ethionic acid being added is 350mg to 1500mg, optional
Ground is 375mg to 1125mg；It is described be stirred to react be 10 DEG C to 60 DEG C range carry out, be optionally 20 DEG C to 50 DEG C；
The time of the stirring is 0.5h to 120h, is optionally 0.5h to 72h；.
Embodiment of the present invention provides (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1-
Base) (3- hydroxy phenyl) methyl) phenyl) and (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph b, the polycrystalline
The X-ray powder diffraction figure of type object B includes the diffraction maximum at following 2 θ value: 15.5 ± 0.2 °, 20.0 ± 0.2 °, 18.6 ±
0.2 °, 5.1 ± 0.2 ° and 19.1 ± 0.2 °.
In one embodiment, the X-ray powder diffraction figure of the polymorph b further includes at selected from the following
Diffraction maximum at one or more 2 θ values of anticipating: 21.3 ± 0.2 °, 20.6 ± 0.2 °, 23.1 ± 0.2 °, 11.4 ± 0.2 °, 16.2
± 0.2 °, 8.8 ± 0.2 °, 13.3 ± 0.2 °, 9.6 ± 0.2 ° and 14.1 ± 0.2 °.
In one embodiment, the polymorph b using differential scanning calorimetry measurement fusing point at 184.5 DEG C extremely
Within the scope of 201.9 DEG C, optionally, about 201.9 DEG C.
In some embodiments, the polymorph b has attached XRPD shown in Fig. 3 figure and attached shown in Fig. 4
TGA and DSC figure.
Embodiment of the present invention provides (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1-
Base) (3- hydroxy phenyl) methyl) phenyl) and (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph b preparation side
Method, comprising:
To (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) first
Base) phenyl) solvent is added in (4- methyl piperidine -1- base) ketone, ethionic acid is then added, low temperature stirring is until be no longer precipitated
Solid filters, dry, obtains the polymorph b.
The solvent is selected from the group being made up of: isopropanol, methanol, ethyl alcohol, propyl alcohol, ethoxy ethanol, 2- methoxyl group
Ethyl alcohol, n-butyl alcohol, 2- butanol, 3- methyl-1-butanol, 2- methyl-1-propyl alcohol, 1- amylalcohol, 1- propyl alcohol, 2- propyl alcohol, in propylene glycol
Any one or more or its any one or more mixed solvent with water.
In one embodiment, relative to (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- bis- described in 2g
Methylpiperazine-1-yl) (3- hydroxy phenyl) methyl) phenyl) (4- methyl piperidine -1- base) ketone, the organic solvent being added
Amount is 15mL to 450mL, is optionally 15mL to 150mL, and the amount for the ethionic acid being added is 350mg to 1500mg, optional
Ground is 375mg to 1125mg；It is described be stirred to react -20 DEG C to 10 DEG C range progress, be optionally 0 DEG C to 5 DEG C；It is described
The time being stirred to react is 0.5h to 120h, is optionally 0.5h to 72h；
The present invention provides (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxyls
Base phenyl) methyl) phenyl) and (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph C, the X- of the polymorph C
Ray powder diffraction pattern includes the diffraction maximum at following 2 θ value: 20.4 ± 0.2 °, 17.1 ± 0.2 °, 18.9 ± 0.2 °, 12.0
± 0.2 ° and 5.7 ± 0.2 °.
In one embodiment, the X-ray powder diffraction figure of the polymorph C further includes at selected from the following
Diffraction maximum at one or more 2 θ values of anticipating: 22.0 ± 0.2 °, 9.5 ± 0.2 °, 18.0 ± 0.2 °, 16.2 ± 0.2 °, 14.1
± 0.2 °, 10.1 ± 0.2 °, 8.9 ± 0.2 °, 23.1 ± 0.2 ° and 11.4 ± 0.2 °.
In one embodiment, the polymorph C using differential scanning calorimetry measurement fusing point at 188.1 DEG C extremely
Within the scope of 206.6 DEG C, optionally, about 206.6 DEG C.
In one embodiment, the polymorph C has attached XRPD shown in fig. 5 figure and attached shown in fig. 6
TGA and DSC figure.
Embodiment of the present invention provides (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1-
Base) (3- hydroxy phenyl) methyl) phenyl) and (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph C preparation side
Method, comprising:
In one embodiment, the polymorph C is heated within the scope of 100 DEG C to 200 DEG C, and optional 100 DEG C extremely
In the range of 150 DEG C；Heating time 2 minutes to 120 minutes, optional 5 minutes to 30 minutes；Natural cooling obtains polymorph
C.In some embodiments of the present invention, described pharmaceutical composition may also include pharmaceutically acceptable carrier or excipient,
The excipient can be conventional functional excipients, such as filler (for example, starch or carbohydrate), adhesive are (for example, micro-
Crystalline cellulose etc.), dispersing agent (for example, anhydrous calcium phosphate, winnofil or calcium silicates etc.).Optionally, the filler is
Mannitol.
In some embodiments of the present invention, described pharmaceutical composition can be made into solid orally ingestible, such as tablet, ball
Agent, capsule and powder agent.
Embodiment of the present invention provides polymorph A described in any embodiment of the present invention, by any reality of the present invention
Apply polymorphic described in the polymorph A, any embodiment of the present invention that the preparation method of polymorph A described in scheme obtains
Object B, the polymorph b as described in any embodiment of the present invention preparation method obtain polymorph b, any reality of the present invention
Apply polymorph C, the polycrystalline that the preparation method of polymorph C obtains as described in any embodiment of the present invention described in scheme
Type object C is preparing the purposes in the drug for preventing or treating mood disorder or disease related with delta opiate receptor.
Embodiment of the present invention provides (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- dimethyl piperazine simultaneously
Piperazine -1- base) (3- hydroxy phenyl) methyl) phenyl) and (4- methyl piperidine -1- base) ketone ethanedisulphonate preparation for prevent or
Treat the purposes in mood disorder or the drug of disease related with delta opiate receptor.
In some embodiments of the present invention, mood disorder disease can be depression；Disease related with delta opiate receptor
Disease can be with are as follows: anxiety disorder, pain, hypoxic-ischemic/reperfusion injury, colitis, optionally ulcerative colitis etc..
Embodiment of the present invention by room temperature at salt, low temperature at salt, heating the methods of be prepared (4- ((R)-((2S,
5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) methyl) phenyl) (4- methyl piperidine -1- base)
Ketone ethanedisulphonate polymorph A, B, C.Three kinds of polymorph solubility height, good absorbing, bioavilability height, toxicity
It is small, stability is good, can effectively prevent and treat depression and other potential diseases, be suitble to new drug exploitation and industrialization
Production.
After reading and understanding attached drawing and detailed description, it can be appreciated that other aspects.
Detailed description of the invention
Attached drawing is to further understand for providing to the embodiment of the present invention, and constitute part of specification, under
The specific embodiment in face is used to explain the present invention embodiment together, but does not constitute the limitation to the embodiment of the present invention.Attached
In figure:
Fig. 1 is (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl)
Methyl) phenyl) (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph A XRPD figure；
Fig. 2 is (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl)
Methyl) phenyl) (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph A TGA and DSC figure；
Fig. 3 is (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl)
Methyl) phenyl) (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph b XRPD figure；
Fig. 4 is (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl)
Methyl) phenyl) (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph b TGA and DSC figure；
Fig. 5 is (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl)
Methyl) phenyl) (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph C XRPD figure；
Fig. 6 is (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl)
Methyl) phenyl) (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph C TGA and DSC figure；
Fig. 7 is dense for the blood medicine that the drug target of more free alkali groups and polymorph A group changes over time in rat plasma
It writes music line chart；
Fig. 8 is the statistical chart that in forced swim test, every group of rat is static, swims and climbs the number that wallflow is.
Specific embodiment
Detailed description of the preferred embodiments below.It should be understood that described herein specific
Embodiment is merely to illustrate and explain the present invention, and is not intended to restrict the invention.
The present invention is further illustrated below with reference to the embodiment of the present invention, unless stated otherwise, used in the embodiment of the present invention
Reagent, raw material be commercial goods.In various embodiments, identical reagent source is identical.
X-ray powder diffraction
X-ray powder diffraction (XRPD) figure of embodiment of the present invention is in PANalytical (Panaco) Empyrean X
It is acquired on ray powder diffraction analysis instrument, XRPD parameter is as follows:
Thermogravimetry and differential scanning calorimetry
Thermogravimetry (TGA) map and differential scanning calorimetry (DSC) map of embodiment of the present invention are respectively in TA
It is acquired on Q500 thermogravimetric analyzer and TA Q200 differential scanning calorimeter, experiment parameter is as follows:
(4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (the 3- hydroxy benzenes of embodiment 1
Base) methyl) phenyl) and (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph A preparation
Take 2g (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) first
Base) phenyl) in (4- methyl piperidine -1- base) ketone to vial, 90mL acetone is added into vial, stirs evenly, then
750mg ethionic acid is added, is stirred at room temperature, reacts 72h, filtering is dry to get (4- ((R)-((2S, 5R) -4- (3- fluorine benzyl
Base)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) methyl) phenyl) (4- methyl piperidine -1- base) ketone ethionic acid
The polymorph A of salt.
(4- ((R)-((2S, the 5R) -4- (3- luorobenzyl)-(2,5- lupetazin-being prepared according to the method described above
1- yl) (3- hydroxy phenyl) methyl) phenyl) and (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph A XRPD figure
As shown in Figure 1, its map peak information is shown in Table 1.The TGA and DSC of polymorph A scheme as shown in Fig. 2, as shown in Figure 2, polymorphic
The fusing point of object A is 185.6 DEG C (from DSC interpretation, its melting range is 174.5 DEG C to 185.6 DEG C).
The XRPD map peak information of 1 polymorph A of table
(4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (the 3- hydroxy benzenes of embodiment 2
Base) methyl) phenyl) and (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph A preparation
Take 2g (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) first
Base) phenyl) in (4- methyl piperidine -1- base) ketone to vial, 15mL tetrahydrofuran is added into vial, stirs evenly,
750mg ethionic acid is then added, 50 DEG C of stirrings are reacted 24 hours, filtering, dry to get (4- ((R)-((2S, 5R) -4-
(3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) methyl) phenyl) (4- methyl piperidine -1- base) ketone second
The polymorph A of disulfonate.
(4- ((R)-((2S, the 5R) -4- (3- luorobenzyl)-(2,5- lupetazin-being prepared according to the method described above
1- yl) (3- hydroxy phenyl) methyl) phenyl) and (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph b XRPD
Figure, TGA and DSC figure are identical as Fig. 1 and Fig. 2 respectively.
(4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (the 3- hydroxy benzenes of embodiment 3
Base) methyl) phenyl) and (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph b preparation
Take 2g (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) first
Base) phenyl) in (4- methyl piperidine -1- base) ketone to vial, 90mL isopropanol is added into vial, stirs evenly, with
750mg ethionic acid is added afterwards, 0 DEG C of stirring is reacted 72 hours, filtering, dry to get (4- ((R)-((2S, 5R) -4- (3- fluorine
Benzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) methyl) phenyl) two sulphur of (4- methyl piperidine -1- base) ketone second
The polymorph b of hydrochlorate.
(4- ((R)-((2S, the 5R) -4- (3- luorobenzyl)-(2,5- lupetazin-being prepared according to the method described above
1- yl) (3- hydroxy phenyl) methyl) phenyl) and (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph b XRPD figure
As shown in figure 3, its map peak information is shown in Table 2.The TGA and DSC of polymorph b scheme as shown in figure 4, as shown in Figure 4, polymorphic
The fusing point of object B is 201.9 DEG C (from DSC interpretation, its melting range is 184.5 DEG C to 201.9 DEG C).
The XRPD map peak information of 2 polymorph b of table
(4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (the 3- hydroxy benzenes of embodiment 4
Base) methyl) phenyl) and (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph C preparation
Take (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- of the embodiment 3 of 2g
Hydroxy phenyl) methyl) phenyl) polymorph b of (4- methyl piperidine -1- base) ketone ethanedisulphonate makees initial sample, it heats
To 150 DEG C, constant temperature for 5 minutes, and to collect obtained solid afterwards be polymorph C.
(4- ((R)-((2S, the 5R) -4- (3- luorobenzyl)-(2,5- lupetazin-being prepared according to the method described above
1- yl) (3- hydroxy phenyl) methyl) phenyl) and (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph C XRPD figure
As shown in figure 5, its map peak information is shown in Table 3.The TGA and DSC of polymorph C schemes as shown in fig. 6, it will be appreciated from fig. 6 that polymorphic
The fusing point of object C is 206.6 DEG C (from DSC interpretation, its melting range is 188.1 DEG C to 206.6 DEG C).
The XRPD map peak information of 3 polymorph C of table
For (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) first
Base) phenyl) (4- methyl piperidine -1- base) ethanedisulphonate polymorph A, B and C, it should be appreciated that for those skilled in the art
For, used solvent can be replaced during the preparation process with experimental actual demand.
Selected from the following group of solvent can be used to be replaced for example, preparing the solvent that polymorph A is used: methyl tert-butyl
Base ketone, methyl isopropyl ketone, hexamethylene, hexahydrotoluene, n-hexane, petroleum ether, ether, methyl tertiary butyl ether(MTBE), 1,4- dioxy six
Ring, methyl ethyl ketone, methyl iso-butyl ketone (MIBK), in methyl pyrrolidone any one or more or acetonitrile, dimethyl formyl
Amine, diethyl acetamide, formamide, methylene chloride, in dimethyl sulfoxide any one or more, dimethyl sulfoxide and water it is mixed
The mixed solvent of bonding solvent or dimethylformamide and water.
Preparing the solvent that polymorph b uses selected from the following group of solvent can be used to be replaced: methanol, ethyl alcohol, third
Alcohol, ethoxy ethanol, 2-methyl cellosolve, n-butyl alcohol, 2- butanol, 3- methyl-1-butanol, 2- methyl-1-propyl alcohol, 1- amylalcohol,
1- propyl alcohol, 2- propyl alcohol, in propylene glycol any one or more or its any one or more mixed solvent with water.
Used quantity of solvent can need to be adjusted according to experiment, the purpose of the application can be achieved, objective does not take off
Design philosophy from embodiment of the present invention, details are not described herein, but should belong in the protection scope of the application.
Test case
(4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy benzenes is measured respectively
Base) methyl) phenyl) (hereinafter referred to as free alkali, and using as reference material, can for the free alkali of (4- methyl piperidine -1- base) ketone
Prepared using existing conventional method) and its ethanedisulphonate polymorph A, B, C (hereinafter referred to as polymorph A, B and C,
Be taken respectively from the sample of embodiment 1,3 and 4) rough solubility, dynamic solubility, relative bioavailability.
(4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy benzenes is measured respectively
Base) methyl) phenyl) and (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph A, B, C (hereinafter referred to as polymorph
A, B and C is taken respectively from the sample of embodiment 1,3 and 4), rough solubility, dynamic solubility.
Rough solubility test
Each 2.0mg of polymorph A, B, C is taken respectively, is respectively placed in the vial of 3.0mL.Then it is gradually added respectively
Solvent methanol, ultrasound simultaneously observe whether sample is completely dissolved.If the still endless fully dissolved of sample then stops after 2.0mL solvent is added
Test, to measure polymorph A, B, C, rough solubility in methyl alcohol respectively.
Using same method, polymorph A, B, C, in table 4 listed other organic solvents or water are measured respectively
In rough solubility.The rough solubility of polymorph A, B, C are displayed in Table 4.
The rough solubility of table 4 polymorph A, B, C
Dynamic solubility test
Free alkali and polymorph A, B, C are measured in water or Biomedia (simulate the gastric juice (SGF), simulation as fed intestines
Liquid (FeSSIF) or simulation fasting state intestinal juice (FaSSIF)) in dynamic solubility.
The preparation of simulate the gastric juice (SGF)
The sodium chloride of 0.2g and the triton x-100 of 0.1g are weighed into 100ml volumetric flask, purified water is added to dissolve, is stirred
After being completely dissolved to solid plus about 135 μ L concentrated hydrochloric acids (37%, 12M), the sodium hydroxide of the hydrochloric acid or 1M of then using 1M adjust pH
To 1.8.Purified water constant volume is finally used, is obtained simulate the gastric juice (SGF), it is spare.
Simulate the preparation of as fed intestinal juice (FeSSIF)
It takes the sodium chloride of the glacial acetic acid of 0.41mL, the sodium hydroxide of 0.20g, 0.59g into 50mL volumetric flask respectively, adds about
The purified water of 48mL dissolves, and pH to 5.0 is adjusted with 1M hydrochloric acid or 1M sodium hydroxide, with purified water constant volume.Then it is added 0.56g's
Powder (simulated intestinal fluids, abbreviation SIF powder, the soybean for being 4:1 by molar ratio of simulated intestinal fluid
Lecithin and natrium taurocholicum composition), it stirs and ultrasound is completely dissolved SIF powder, obtain simulation as fed intestinal juice
(FeSSIF), spare.
Simulate the preparation of fasting state intestinal juice (FaSSIF)
Sodium dihydrogen phosphate (the NaH of 0.17g is weighed respectively2PO4, it is anhydrous), the sodium hydroxide of 0.021g, 0.31g sodium chloride
Into 50mL volumetric flask, the purified water of about 48ml is added to dissolve, adjusts pH to 6.5 with the hydrochloric acid of 1M or the sodium hydroxide of 1M, use is pure
Change water constant volume.Then the SIF powder of 0.11g is added, stirs and ultrasound is completely dissolved powder, obtains simulation fasting state intestinal juice
(FaSSIF), spare.
Free alkali, each 30mg of polymorph A, B, C are weighed respectively, and the purified water, simulate the gastric juice (SGF), simulation of 3mL is added
As fed intestinal juice (FeSSIF) or simulation fasting state intestinal juice (FaSSIF)), shaken at room temperature, on the time point of setting, often
The secondary suspension for taking out 0.6mL, after being separated by filtration with 0.45 micron of nylon leaching film, solid sample carries out XRPD characterization, clear liquid
In concentration be measured with HPLC.Table 5 shows the dynamic solubility of polymorph A, B, C, the pH in clear liquid.
The crystal form of pH and not molten solid sample in the dynamic solubility of table 5 polymorph A, B, C, clear liquid
After tested, as can be drawn from Table 5, compared with free alkali, at the ethanedisulphonate after salt polymorph A, B and
C is in water, simulate the gastric juice (SGF), simulation as fed intestinal juice (FeSSIF) and simulates molten in fasting state intestinal juice (FaSSIF)
Xie Du is significantly improved.
Bioavailability study
The blood concentration of drug target in SPF grades of SD rat plasmas is detected using the method for HPLC-MS/MS, and to rat
The Relative biological of the suspension of free alkali -0.5%CMC-Na and the 0.5%CMC-Na solution of polymorph A is given in stomach-filling respectively
Availability is calculated and compared.
The preparation of the 0.5%CMC-Na suspension of the drug target of free alkali group: precision weighs free alkali 60.40mg and is placed in
In 15mL centrifuge tube, 0.5%CMC-Na solution 12mL is measured into centrifuge tube with graduated cylinder, vortex 5min, ultrasonic 15min make to disperse
Uniformly to get concentration be 5.04mg/ml free alkali 0.5%CMC-Na suspension, it is ready-to-use and during the administration with
When shake.
The preparation of the 0.5%CMC-Na solution of the drug target of polymorph A group: precision weighs the polymorphic of 60.02mg
Object A is placed in 15mL centrifuge tube, measures 0.5%CMC-Na solution 12mL into centrifuge tube with graduated cylinder, vortex 5min, ultrasound
15min makes the 0.5%CMC-Na solution being uniformly dispersed to get the polymorph A of 5.00mg/mL, ready-to-use.
SPF grades SD rat 12 are selected, is randomly divided into free alkali group, polymorph A group, every group 6 (male and female dual-purpose).It is dynamic
Object is deprived of food but not water about 12h, and weighing calculates the administered volume of every rat according to the weight of animals, making dosage is 20mg/
kg.bw.When administration, gastric infusion, the 0.5%CMC-Na for extracting above two drug target respectively with 2mL syringe are mixed respectively
Gastric perfusion needle is pushed into solution from rat bicker place insertion stomach by suspension/solution.
Before administration 0.5,1,2,4,6,8,12 and for 24 hours after (0h) and administration, blood is taken in rat eyeground vein clump
0.2mL, it is anticoagulant with 300IU/mL heparin (1:20), it is centrifuged (3000r/min) 15min.It is surveyed after separated plasma with HPLC-MS/MS
Set the goal drug blood concentration, and the blood concentration-time curve of acquisition is shown in Fig. 7.Two groups main is calculated to obtain with DAS2.0 software
Medicine is shown in Table 6 for parameter.
The average medicine of 6 free alkali A group of table and the polymorph b group of ethanedisulphonate is for parameter
Average AUC (0-24h) A of free alkali group is 288.6ng/mL*h, average AUC (0-24h) B of polymorph b group
For 600.3ng/mL*h, relative bioavailability (F) is calculated as follows:
I.e. under this experiment condition, polymorph A is 208% relative to the bioavilability of free alkali.Joined according to medicine generation
Digital display shows that polymorph A aqueous solution reaches peak faster, and average out to Cmax is higher.
Referring to the bioavailability study of above-mentioned polymorph A, polymorph b and the bioavilability examination of C are carried out respectively
It tests.Be with the bioavailability study difference of polymorph A: to rat, stomach-filling gives the 0.5% of polymorph b or C respectively
CMC-Na solution, other operations are identical as above-mentioned bioavailability study.The 0.5% of obtained result and polymorph A
CMC-Na solution result is consistent, and relative to free alkali, bioavilability is more preferable by polymorph b and C.
Polymorph A, B and C are improved compared with the dynamic solubility of free alkali, into animal body in be easier to through cell membrane, more
It is easily absorbed, so that bioavilability is higher.
1 forced swimming test of Application Example
Using forced swimming test, the effect in terms of antidepressant effect of polymorph A, B, C are tested.
(1) specific experimental enviroment: the transparent glass circle cylinder that swimming test equipment is 46cm high, interior diameter is 20cm, test
Water temperature is 23 DEG C~25 DEG C, and the test depth of water is 30cm, and every cylinder water is only used once.
(2) preparation of specific reagent
Vehicle controls liquid: 0.9% physiological saline.
It tests the preparation of one group of experiment reagent: weighing the polymorph b of 350mg with electronic balance, and use 0.9%
Physiological saline dissolves polymorph b, is finally settled to 100mL with 0.9% physiological saline, at this time second in experiment reagent
The concentration of disulfonate is 3.5mg/mL, spare.
It tests the preparation of two groups of experiment reagent: weighing the polymorph b of 700mg with electronic balance, and use 0.9%
Physiological saline dissolves polymorph b, is finally settled to 100mL with 0.9% physiological saline, at this time second in experiment reagent
The concentration of disulfonate is 7mg/mL, spare.
The preparation of positive control solution: the desipramine (DMI) of 400mg is weighed with electronic balance, with 0.9% physiological saline
DMI is dissolved, is then settled to 100mL with 0.9% physiological saline, it is spare.
(3) test method
Prepare SPF grades SD rat 40, is randomly divided into 4 groups, i.e. vehicle control group, positive controls, one group of experiment, experiment
Two groups, every group 10.Test the previous day, by rat, 15min to swim 15min in advance into the water, to adapt to the environment of swimming test,
It then takes out and dries, be put in cage and set 15min under infrared lamp and place into former mouse cage.Carry out formal swimming test afterwards for 24 hours, i.e.,
Rat is reentered into water after for 24 hours, 5min is observed continuously, swimming process need to be imaged.It is administered during swimming twice.
(4) capacity and dosage, approach and period is administered
According to shown in table 7 administration capacity and approach be administered.
The capacity (dosage) and approach of each group of table 7 administration
Positive controls containing DMI are administered three times, and the abdominal cavity 23.5h, 5h and 1h is infused before formal swimming test
Penetrate administration；Two groups of vehicle control group, one group of experiment and experiment are only administered once respectively, in 1h subcutaneous administrations.
(5) behavior scoring
At interval of 5 seconds, scoring person scored to rat behavior for the video recording of test process.
Following three behaviors are recorded:
1) static-when rat floats on the water surface, it does not struggle, movement is then evaluated merely to its head is kept to expose the surface
Rat is static；
2) apparent swimming behavior is swum-had rather than just in order to keep head to expose the surface, or in circle cylinder middle ring
Trip evaluates rat then as swimming；
3) behavior that wall-rat fore paw has the obvious disengaging water surface is climbed, usually before circle casing wall, then evaluating rat is to climb wall.
All behavior scorings are carried out by single, and for the skewed popularity for avoiding observation, scoring person is not only knowing about administrations
Under conditions of observed, score.Several test segments are randomly selected again, and the second wheel scoring is carried out by scoring person and is observed with determining
Accuracy.Test video recording is scored by second scoring person again to determine the accuracy between scoring person, second scoring
Person also requires to observe in the case where not knowing about administrations, finally in order to determine the validity of method, again by first scoring person
Secondary scoring, and with stopwatch record various actions duration.
(6) statistical method
Variance analysis is carried out using SPSSwin11.0 software, variance uses one-way analysis of variance together, and heterogeneity of variance uses
Dunnett is examined.
(7) test result
According to the record result and statistical method of above-mentioned behavior scoring, following tests result is obtained.
8 every groups of rats of table are static, swim and climb the number that wallflow is
Note: compared with vehicle control group:▲P < 0.05,▲▲P < 0.01,▲▲▲p<0.001。
Table 8 and Fig. 8's the result shows that: give the positive that rat contains the positive control solution of 40mg/kg desipramine (DMI)
Control group can reduce the static number of rat, increase rats'swimming number, and wall number is climbed in increase, compared with vehicle control group, tool
There is significant difference (P < 0.001, P < 0.01, P < 0.05)；Show that test method is feasible.Rat is given respectively contains 35mg/kg
It is quiet that two groups of one group of experiment and experiment with the experiment reagent of the polymorph b of 70mg/kg can obviously reduce rat antidepressant effect
Only number, increase rats'swimming number, increase climb wall number, compared with vehicle control group, have significant difference (P <
0.001, P < 0.05, P < 0.05).
9 every groups of rats of table are static, swim and climb the duration that wallflow is
Note: compared with vehicle control group:▲P < 0.05,▲▲P < 0.01,▲▲▲p<0.001。
Table 9 the result shows that: give the positive control that rat contains the positive control solution of 40mg/kg desipramine (DMI)
Group can reduce rat quiescent duration, increase the rats'swimming duration, the wall duration is climbed in increase, with vehicle control group phase
Compare, has significant difference (P < 0.001, P < 0.01, P < 0.01)；Show that test method is feasible.Rat is given respectively to contain
It is mandatory that two groups of one group of the experiment of the experiment reagent of the polymorph b of 35mg/kg and 70mg/kg and experiment can obviously reduce rat
Swimming quiescent duration increases the rats'swimming duration, and the wall duration is climbed in increase, compared with vehicle control group, tool
There is significant difference (P < 0.001, P < 0.05, P < 0.05).
Experiments have shown that polymorph b has better antidepressant effect.
Referring to the forced swimming test of above-mentioned polymorph b, the forced swimming test of polymorph A, C are carried out respectively.With
The forced swimming test difference of polymorph b is: take polymorph A or C to replace polymorph b preparation experiment reagent, other
It operates identical as above-mentioned forced swimming test.Obtained result is consistent with polymorph b aqueous solution result, polymorph A, C
The static times and duration of rat antidepressant effect can be effectively reduced, increases rats'swimming times and duration, increase
Climb wall times and duration.
Present disclosure is the example of the principle of the embodiment of the present application, is not made to the application in any form or substantive
On restriction, or the application is limited to specific embodiment.It will be apparent to those skilled in the art that the application is real
Element, compound, polymer, ingredient, composition, preparation, the process etc. for applying the technical solution of example, can be changed,
Change, change, develop, without departing from embodiments herein as described above, technical solution, as defined in the claims
Principle, spirit and scope.These variations, the embodiment for changing, changing, developing are included in the equivalent integers of the application
Interior, these equivalent integers are included in the range of being defined by the claims of the application.Although can be in many different forms
Embody the embodiment of the present application, but what is be described in detail herein is some embodiments of the invention.In addition, the reality of the application
Apply some or all of any possible combination that example includes various embodiments described herein, be also included within the application by
In the range of claim defines.In this application or any one reference patent, reference patent application or other references
Data in Anywhere mentioned all patents, patent application and other citations are whole simultaneously with it accordingly by reference
Enter.
Above disclosure is defined as illustrative rather than exhaustive.To those skilled in the art, this theory
The bright gathering of calligraphers implies many variations and optional scheme.All these optional schemes and variation are intended to be included in present claims
In the range of, wherein term " includes " means " including, but are not limited to ".
The description to alternate embodiment of the present invention is completed herein.One skilled in the art will recognize that this place
The other equivalent transformations for the embodiment stated, these equivalent transformations are also as investing included by the claims herein.
Industrial applicibility
(4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- that embodiment of the present invention provides
Base) (3- hydroxy phenyl) methyl) phenyl) (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph A, B, C, have molten
The features such as solution degree height, good absorbing, bioavilability height, small toxicity, good stability, can effectively prevent and treat depression with
And other potential diseases, it is suitble to the exploitation and industrialized production of new drug.In addition, three kinds of polymorphics that embodiment of the present invention provides
Preparation method is simple for object, is suitble to industrialized production.
Claims (22)
1. (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) methyl) benzene
Base) (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph A, the X-ray powder diffraction figure of the polymorph A
Including the diffraction maximum below at 2 θ values: 12.1 ± 0.2 °, 19.0 ± 0.2 °, 16.8 ± 0.2 °, 18.2 ± 0.2 ° and 20.3 ±
0.2°；
The X-ray powder diffraction figure of the polymorph A further includes the diffraction maximum at 2 θ value below: 19.5 ± 0.2 °, 12.9
± 0.2 °, 17.6 ± 0.2 °, 4.9 ± 0.2 °, 16.2 ± 0.2 °, 8.8 ± 0.2 °, 7.3 ± 0.2 ° and 9.7 ± 0.2 °.
2. polymorph A as described in claim 1, wherein the polymorph A is molten using differential scanning calorimetry measurement
O'clock within the scope of 174.5 DEG C -185.6 DEG C.
3. polymorph A as claimed in claim 2, wherein the polymorph A is molten using differential scanning calorimetry measurement
Point is 185.6 DEG C.
4. polymorph A as claimed in any one of claims 1-3, wherein the polymorph A has shown in FIG. 1
XRPD figure and TGA shown in Fig. 2 and DSC figure.
5. (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- as described in claim 1
Hydroxy phenyl) methyl) phenyl) and (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph A preparation method, comprising:
To (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) methyl) benzene
Base) organic solvent is added in (4- methyl piperidine -1- base) ketone, ethionic acid is then added, stirring until no longer wash out solid,
Filtering, it is dry, the polymorph A is obtained,
The organic solvent is acetone or tetrahydrofuran.
6. preparation method as claimed in claim 5, relative to (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-described in 2g
(2,5- lupetazin -1- base) (3- hydroxy phenyl) methyl) phenyl) (4- methyl piperidine -1- base) ketone, what is be added is organic
The amount of solvent is 15mL-450mL；The amount for the ethionic acid being added is 350mg-1500mg；The time being stirred to react is
0.5h-120h；Reaction temperature is 10 DEG C -60 DEG C.
7. preparation method as claimed in claim 6, relative to (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-described in 2g
(2,5- lupetazin -1- base) (3- hydroxy phenyl) methyl) phenyl) (4- methyl piperidine -1- base) ketone, what is be added is organic
The amount of solvent is 15mL-150mL；
And/or the amount for the ethionic acid being added is 375mg-1125mg；
And/or the time being stirred to react is 0.5h-72h；And/or reaction temperature is 20 DEG C -50 DEG C.
8. (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) methyl) benzene
Base) (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph b preparation method, comprising:
To (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) methyl) benzene
Base) solvent is added in (4- methyl piperidine -1- base) ketone, ethionic acid is then added, low temperature stirring until solid is no longer precipitated,
Filtering, it is dry, the polymorph b is obtained,
The solvent is isopropanol；
The X-ray powder diffraction figure of the polymorph b includes the diffraction maximum at following 2 θ value: 15.5 ± 0.2 °, 20.0 ±
0.2 °, 18.6 ± 0.2 °, 5.1 ± 0.2 ° and 19.1 ± 0.2 °；
The X-ray powder diffraction figure of the polymorph b further includes the diffraction maximum at 2 θ value below: 21.3 ± 0.2 °, 20.6
± 0.2 °, 23.1 ± 0.2 °, 11.4 ± 0.2 °, 16.2 ± 0.2 °, 8.8 ± 0.2 °, 13.3 ± 0.2 °, 9.6 ± 0.2 ° and 14.1
±0.2°。
9. preparation method as claimed in claim 8, wherein the polymorph b is molten using differential scanning calorimetry measurement
O'clock within the scope of 184.5 DEG C -201.9 DEG C.
10. preparation method as claimed in claim 9, wherein the polymorph b is molten using differential scanning calorimetry measurement
Point is 201.9 DEG C.
11. preparation method as claimed in claim 8, wherein the polymorph b is schemed with XRPD shown in Fig. 3, Yi Jitu
TGA shown in 4 and DSC figure.
12. preparation method as claimed in claim 8, relative to (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-described in 2g
(2,5- lupetazin -1- base) (3- hydroxy phenyl) methyl) phenyl) (4- methyl piperidine -1- base) ketone, the solvent being added
Amount be 15mL-450mL；The amount for the ethionic acid being added is 350mg-1500mg；The time being stirred to react is 0.5h-
120h；Reaction temperature is -20 DEG C -10 DEG C.
13. preparation method as claimed in claim 12, relative to (4- ((R)-((2S, 5R) -4- (3- fluorine benzyl described in 2g
Base)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) methyl) phenyl) (4- methyl piperidine -1- base) ketone, it is added
The amount of solvent is 15mL-150mL；
And/or the amount for the ethionic acid being added is 375mg-1125mg；
And/or the time being stirred to react is 0.5h-72h；
And/or reaction temperature is 0 DEG C -5 DEG C.
14. (4- ((R)-((2S, 5R) -4- (3- luorobenzyl)-(2,5- lupetazin -1- base) (3- hydroxy phenyl) methyl) benzene
Base) (4- methyl piperidine -1- base) ketone ethanedisulphonate polymorph C preparation method, comprising:
It will be heated within the scope of 100 DEG C -200 DEG C such as the described in any item polymorph bs of claim 8-13；Heating time 2 divides
Clock -120 minutes；Natural cooling obtains polymorph C；
The X-ray powder diffraction figure of the polymorph C includes the diffraction maximum at following 2 θ value: 20.4 ± 0.2 °, 17.1 ±
0.2 °, 18.9 ± 0.2 °, 12.0 ± 0.2 ° and 5.7 ± 0.2 °；
The X-ray powder diffraction figure of the polymorph C further includes the diffraction maximum at 2 θ value below: 22.0 ± 0.2 °, 9.5
± 0.2 °, 18.0 ± 0.2 °, 16.2 ± 0.2 °, 14.1 ± 0.2 °, 10.1 ± 0.2 °, 8.9 ± 0.2 °, 23.1 ± 0.2 ° and
11.4±0.2°。
15. preparation method as claimed in claim 14, wherein the polymorph C utilizes differential scanning calorimetry measurement
Fusing point is within the scope of 188.1 DEG C -206.6 DEG C.
16. preparation method as claimed in claim 15, wherein the polymorph C utilizes differential scanning calorimetry measurement
Fusing point is 206.6 DEG C.
17. preparation method as claimed in claim 14, wherein the polymorph C schemes with XRPD shown in fig. 5, and
TGA and DSC figure shown in fig. 6.
18. preparation method as claimed in claim 14, wherein will be such as the described in any item polymorph bs of claim 8-13
It is heated in the range of 100 DEG C -150 DEG C；
And/or heating time is -30 minutes 5 minutes.
19. a kind of pharmaceutical composition, comprising such as polymorph A of any of claims 1-4 or by such as claim
Polymorph A that preparation method described in any one of 5-7 obtains, as the preparation side as described in any one of claim 8-13
In polymorph b that method obtains, the polymorph C obtained as the preparation method as described in any one of claim 14-18
It is at least one.
20. pharmaceutical composition as claimed in claim 19 further includes pharmaceutically acceptable carrier or excipient.
21. such as polymorph A of any of claims 1-4 or as the system as described in any one of claim 5-7
Polymorph A that Preparation Method obtains, the polymorph b obtained as the preparation method as described in any one of claim 8-13,
It is being prepared as the polymorph C that the preparation method as described in any one of claim 14-18 obtains for preventing or treating the heart
Purposes in border obstacle or the drug of disease related with delta opiate receptor.
22. purposes as claimed in claim 21, wherein the mood disorder disease is depression.
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Application publication date: 20170426 Assignee: Yunnan Baiyao Group Co.,Ltd. Assignor: YUNNAN INSTITUTE OF MATERIA MEDICA Contract record no.: X2022530000005 Denomination of invention: A polymorphic form of triaryldimethylpiperazine ethyldisulfonate and its preparation method and Application Granted publication date: 20191112 License type: Common License Record date: 20220624 |