CN106588874A - Polymorphic substance of triarylated dimethylpiperazine di-hydrochloride and preparation method and application thereof - Google Patents
Polymorphic substance of triarylated dimethylpiperazine di-hydrochloride and preparation method and application thereof Download PDFInfo
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- CN106588874A CN106588874A CN201611039151.3A CN201611039151A CN106588874A CN 106588874 A CN106588874 A CN 106588874A CN 201611039151 A CN201611039151 A CN 201611039151A CN 106588874 A CN106588874 A CN 106588874A
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- C—CHEMISTRY; METALLURGY
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses four polymorphic substances B, E, H and D of (4-((R)-((2S, 5R)-4-(3-fluorobenzyl)-(2,5-dimethylpiperazine-1-base)(3-hydroxyphenyl)methyl)phenyl)(4-methylpiperidine-1-base)ketone di-hydrochloride, a preparation method thereof, and application in preparing a drug.
Description
Technical field
The present invention relates to, but not limited to pharmaceutical technology field, specifically, relates to, but are not limited to a kind of triaryl dimethyl
Polymorph of piperazine dihydrochloride and its preparation method and application.
Background technology
Depression is a kind of common mental sickness, is mainly shown as depressed, and interest lowers, pessimistic, retardation of thinking,
Lack initiative, from crime, diet, sleep are poor, worry oneself with various diseases, feel that whole body many places are uncomfortable, severe patient for self-accusation
May occur in which suicidal thought and behavior." the Diagnostic and Statistical Manual that APA,American Psychiatric Association publishes
of Mental Disorders”《Psychosiss diagnostic and statistical manual》In fourth edition, depression is classified under mood disorders,
It is divided into three types：Major depressive disorder, dysthymic disorder and other unspecified depressions.
Causing the factor of depression includes：Inherited genetic factorss, physical factors, the function of nervus centralis media and Developmental and Metabolic Disorder,
Nervous and Mental Factors etc..In the effort for the treatment of depression, various antidepressant compositions are had been developed, for example, color Qu Lin, Fu Luoxi
Spit of fland, paroxetine, fluvoxamine, BUP.Although effectively, Jing often produces problematic side effect to these medicines, such as
Lethargy, confusion of thinking, can not focus on and sexual dysfunction.Also, these medicines have that onset time is long,
Needed for about 6 to 8 weeks can just show any desired therapeutic effect.
The content of the invention
The following is the general introduction of the theme to describing in detail herein.This general introduction is not to limit the protection model of claim
Enclose.
Present inventor's Jing lot of experiments, it is found that triaryl lupetazin compound can increase from different approaches
Strong effect of the opioid recdptor in depression, and therefore it is theoretical based on opioid receptor δ-receptor, according to antidepressant activity
The ad-hoc location of δ-receptor, for the action target spot δ-receptor of depression, develops with the δ-receptor agonism of following formula I structure
Agent triaryl lupetazin compound (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases)
(3- hydroxy phenyls) methyl) phenyl) (4- methyl piperidine -1- bases) ketone dihydrochloride (molecular formula：C33H42FCl2N3O2, molecule
Amount：602.69) and its polymorph, and plan its exploitation be the new drug with antidepressant effect and other potential effects into
Point.
Embodiment of the present invention provides (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1-
Base) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride 4 kinds of polymorphs, i.e. polymorphic
Thing B, polymorph E, polymorph H, polymorph D.
Embodiment of the present invention additionally provide (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazins -
1- yls) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride 4 kinds of polymorphs, i.e. polycrystalline
The preparation method of type thing B, polymorph E, polymorph H and polymorph D.
Embodiment of the present invention additionally provides (4- ((R)-((2S, the 5R) -4- by described in any embodiment of the present invention
(3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyls) methyl) phenyl) (4- methyl piperidine -1- bases) ketone two
4 kinds of polymorphs of hydrochlorate, i.e. the preparation method system of polymorph b, polymorph E, polymorph H and polymorph D
The polymorph for obtaining.
Embodiment of the present invention is additionally provided comprising (4- ((R)-((2S, the 5R) -4- described in any embodiment of the present invention
(3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyls) methyl) phenyl) (4- methyl piperidine -1- bases) ketone two
At least one in 4 kinds of polymorphs of hydrochlorate, i.e. polymorph b, polymorph E, polymorph H and polymorph D
Pharmaceutical composition.
Embodiment of the present invention additionally provides (4- ((R)-((2S, the 5R) -4- (3- described in any embodiment of the present invention
Luorobenzyl)-(2,5- lupetazin -1- bases) (3- hydroxy phenyls) methyl) phenyl) (4- methyl piperidine -1- bases) ketone disalt
The polymorph b of hydrochlorate, polymorph E, the purposes of polymorph H and polymorph D.
Embodiment of the present invention provides (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1-
Base) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph b, the polymorphic
The X-ray powder diffraction figure of thing B includes the following diffraction maximum at 2 θ values：17.6±0.2°、8.0±0.2°、23.6±
0.2 °, 13.0 ± 0.2 ° and 9.2 ± 0.2 °.
In one embodiment, the X-ray powder diffraction figure of the polymorph b is additionally included in and appoints selected from following
Diffraction maximum at one or more 2 θ values of anticipating：19.8±0.2°、15.6±0.2°、14.6±0.2°、25.4±0.2°、11.7
± 0.2 °, 26.7 ± 0.2 °, 19.4 ± 0.2 °, 22.5 ± 0.2 °, 16.8 ± 0.2 ° and 18.4 ± 0.2 °.
In one embodiment, the polymorph b using differential scanning calorimetry determine fusing point 154.4 DEG C-
In the range of 171.6 DEG C, alternatively, about 171.6 DEG C.
In some embodiments, the polymorph b has the XRPD figures shown in accompanying drawing 1, and shown in accompanying drawing 2
TGA and DSC schemes.
Embodiment of the present invention provides (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1-
Base) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph b preparation method
For：
To (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyls) first
Base) phenyl) organic solvent is added in (4- methyl piperidine -1- bases) ketone, concentrated hydrochloric acid solution is subsequently added, stirring is until no longer analyse
Go out solid, filter, be dried, obtain the polymorph b,
Wherein, solvent is selected from group consisting of in the preparation method：Acetone, methyl iso-butyl ketone (MIBK), methyl isopropyl
Ketone, hexamethylene, hexahydrotoluene, normal hexane, petroleum ether, ether, methyl tertiary butyl ether(MTBE), 1,4- dioxane, methyl ethyl ketone,
Any one in methyl iso-butyl ketone (MIBK), methyl pyrrolidone or more kinds of, or ethyl acetate, butyl acetate, Ethyl formate, second
In sour isobutyl ester, isopropyl acetate, methyl acetate, propyl acetate any one or it is more kinds of.
In one embodiment, relative to (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- bis- described in 10g
Methylpiperazine-1-yl) (3- hydroxy phenyls) methyl) phenyl) (4- methyl piperidine -1- bases) ketone, the organic solvent for being added
Measure as 50mL-1000mL, be optionally 50mL-300mL, the amount of the concentrated hydrochloric acid for being added is 1.5mL-7.0mL, is optionally
1.75mL-5.25mL；The time of the stirring reaction is 0.5h-12h, is optionally 2h-4h；Reaction temperature is 10 DEG C -40 DEG C.
Embodiment of the present invention provides (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1-
Base) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph E, the polymorphic
The X-ray powder diffraction figure of thing E includes the following diffraction maximum at 2 θ values：14.8±0.2°、12.7±0.2°、8.2±
0.2 °, 18.2 ± 0.2 ° and 13.1 ± 0.2 °.
In one embodiment, the X-ray powder diffraction figure of the polymorph E is additionally included in and appoints selected from following
Diffraction maximum at one or more 2 θ values of anticipating：26.6±0.2°、15.1±0.2°、25.3±0.2°、13.3±0.2°、23.6
±0.2°、21.9±0.2°、11.7±0.2°、9.2±0.2°、19.2±0.2°、27.3±0.2°、16.3±0.2°、20.8
± 0.2 °, 27.9 ± 0.2 °, 29.4 ± 0.2 ° and 21.3 ± 0.2 °.
In one embodiment, the polymorph E using differential scanning calorimetry determine fusing point 161.1 DEG C-
In the range of 170.4 DEG C, it is preferable that about 170.4 DEG C.
In some embodiments, the polymorph E has the XRPD figures shown in accompanying drawing 3, and shown in accompanying drawing 4
TGA and DSC schemes.
Embodiment of the present invention provides (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1-
Base) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph E preparation method
For：
By the polymorph b described in any embodiment of the present invention, vial is positioned over；It is positioned over this vial is open
In carboy equipped with solvent；Place 5 days under the conditions of the closed room temperature of carboy, taking-up solid, as polymorph E,
In one embodiment, the solvent is selected from group consisting of：Acetonitrile, dimethylformamide, diethyl
In acetamide, Methanamide, dichloromethane, dimethyl sulfoxide, tetrahydrofuran any one or it is more kinds of.
Embodiment of the present invention provides (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1-
Base) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph H, the polymorphic
The X-ray powder diffraction figure of thing H includes the diffraction maximum at following 2 θ values：12.9±0.2°、8.0±0.2°、17.6±0.2°、
23.4 ± 0.2 ° and 14.5 ± 0.2 °.
In one embodiment, the X-ray powder diffraction figure of the polymorph H is additionally included in and appoints selected from following
Diffraction maximum at one or more 2 θ values of anticipating：9.1±0.2°、25.3±0.2°、16.8±0.2°、26.5±0.2°、19.5
±0.2°、11.6±0.2°、22.5±0.2°、15.4±0.2°、13.3±0.2°、19.8±0.2°、22.0±0.2°、26.1
± 0.2 ° and 27.4 ± 0.2 °.
In one embodiment, the polymorph H using differential scanning calorimetry determine fusing point 166.8 DEG C-
In the range of 172.0 DEG C, it is preferable that about 172.0 DEG C.
In some embodiments, the polymorph H has the XRPD figures shown in accompanying drawing 5, and shown in accompanying drawing 6
TGA and DSC schemes.
Embodiment of the present invention provides (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1-
Base) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph H preparation method,
Including：
(1) by the polymorph b described in any embodiment of the present invention, solvent is added to be completely dissolved solid；Slow drop
Methylate isobutyl ketone is to generating precipitation.By precipitate and separate, as polymorph H；Or
(2) polymorph b described in any embodiment of the present invention is positioned over into vial；By the open placement of this vial
In the carboy equipped with solvent；After carboy is placed in confined conditions, solid, as polymorph H are taken out；Or
(3) polymorph b described in any embodiment of the present invention is positioned in the open glass bottle equipped with solvent；
To suspension, after stirring under certain room temperature condition, centrifugation solid is polymorph H；Or
(4) polymorph b described in any embodiment of the present invention is positioned in open glass bottle；Add chloroform with just
Heptane mixed solvent (mixed proportion 1:9) suspension is obtained, after stirring under the conditions of uniform temperature, centrifugation solid is many
Crystal formation thing H,
In one embodiment, in preparation method (1), the solvent is selected from group consisting of：Acetonitrile, diformazan
In base Methanamide, diethyl acetamide, Methanamide, dichloromethane, dimethyl sulfoxide, tetrahydrofuran any one or it is more kinds of；
In method (2)-(3), the solvent selected from add 2- methyltetrahydrofurans or Isosorbide-5-Nitrae-dioxane or dichloromethane or ethanol with
Toluene Mixed Solvent (mixed proportion 1:Or chloroform and normal heptane mixed solvent (mixed proportion 1 9):9).
In one embodiment, in method (1)-(4), relative to 1.5g polymorph bs, the solvent for being added
Amount be 50mL-1000mL, be chosen as 50mL-300mL；Separately, in method (2)-(4), temperature required is 10 DEG C -80 DEG C, excellent
25 DEG C or 50 DEG C are selected, mixing time is -10 days 1 day, is optionally 4 days；Described in method (3) under the conditions of closed room temperature
Place -7 days 1 day, be optionally 5 days；In method (4), described standing is -7 days 1 day, is optionally 3 days.
Embodiment of the present invention provides (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1-
Base) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph D, the polymorphic
The X-ray powder diffraction figure of thing D includes the following diffraction maximum at 2 θ values：17.7±0.2°、20.1±0.2°、13.0±
0.2 °, 8.9 ± 0.2 ° and 16.2 ± 0.2 °.
Polymorph D described in one embodiment, wherein, the X-ray powder diffraction figure of the polymorph D
The diffraction maximum being additionally included at following any one or more 2 θ values：7.8±0.2°、15.7±0.2°、22.4±
0.2 °, 19.5 ± 0.2 °, 25.4 ± 0.2 °, 29.0 ± 0.2 °, 31.7 ± 0.2 ° and 14.8 ± 0.2 °.
Polymorph D described in one embodiment, wherein, the polymorph D utilizes differential scanning calorimetry
The fusing point of measure is in the range of 171.8 DEG C -178.1 DEG C, it is preferable that about 178.1 DEG C.
Polymorph D described in some embodiments, wherein, the polymorph D has the XRPD shown in accompanying drawing 7
Figure, and the TGA shown in accompanying drawing 8 and DSC figures.
Embodiment of the present invention provides (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1-
Base) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph D preparation method,
Including：
(1) by 100mg 4- ((α R)-α-((2S, 5R) -4- (3- luorobenzyls) -2,5- dimethyl -1- piperazinyls)-(3- hydroxyls
Base benzyl))-(4- methyl isophthalic acids-piperidyl)-ketone be added in organic solvent mix；Concentrated hydrochloric acid (37.5%), stirring are added afterwards
After reaction, vacuum drying obtains final product polymorph D；Or
(2) by the polymorph E described in any embodiment of the present invention, 100 DEG C are heated to, it is naturally cold under nitrogen protection
But polymorph D is obtained to room temperature；Or
(3) by the polymorph H described in any embodiment of the present invention, 100 DEG C are heated to, it is naturally cold under nitrogen protection
But polymorph D is obtained to room temperature；Or
(4) by the polymorph b described in any embodiment of the present invention, 100 DEG C are heated to, it is naturally cold under nitrogen protection
But polymorph D is obtained to room temperature,
Wherein in preparation method (1), the organic solvent is selected from：Acetone, methyl iso-butyl ketone (MIBK), methyl isopropyl ketone, ring
Hexane, hexahydrotoluene, normal hexane, petroleum ether, ether, methyl tertiary butyl ether(MTBE), 1,4- dioxane, methyl ethyl ketone, methyl
In isobutyl ketone, methyl pyrrolidone any one or it is more kinds of.
Preparation method described in one embodiment, wherein, in method (1), relative to (4- described in 100mg
((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyls) methyl) phenyl) (4- methyl
Piperidin-1-yl) ketone, the amount of the organic solvent for being added is 0.5mL-10mL, is optionally 0.5mL-3mL, and what is added is dense
The amount of hydrochloric acid is 10mL-100mL, is optionally 30mL-40mL；The time of the stirring reaction is 0.5h-12h, is optionally
2h-4h；Reaction temperature is 10 DEG C -40 DEG C.
Embodiment of the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes arbitrary embodiment party of the invention
The polymorphic that the preparation method of the polymorph b described in case or the polymorph b by described in any embodiment of the present invention is obtained
Polymorph E's described in thing B, any embodiment of the present invention or polymorph E by described in any embodiment of the present invention
Polymorph H described in polymorph E that preparation method is obtained, any embodiment of the present invention or by arbitrary embodiment party of the invention
Polymorph D described in polymorph H that the preparation method of the polymorph H described in case is obtained, any embodiment of the present invention
Or at least one in the polymorph D that obtains of the preparation method of the polymorph D by described in any embodiment of the present invention.
In some embodiments of the present invention, described pharmaceutical composition may also include pharmaceutically acceptable carrier or tax
Shape agent, the excipient can be conventional feature excipient, such as filler (for example, starch or saccharide etc.), binding agent (example
Such as, Microcrystalline Cellulose etc.), dispersant (for example, anhydrous calcium phosphate, winnofil or calcium silicates etc.).Alternatively, the filling
Agent 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 or powder agent.
Embodiment of the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition includes arbitrary embodiment party of the invention
The polymorphic that the preparation method of the polymorph b described in case or the polymorph b by described in any embodiment of the present invention is obtained
Polymorph E's described in thing B, any embodiment of the present invention or polymorph E by described in any embodiment of the present invention
Polymorph H described in polymorph E that preparation method is obtained, any embodiment of the present invention or by arbitrary embodiment party of the invention
Polymorph D described in polymorph H that the preparation method of the polymorph H described in case is obtained, any embodiment of the present invention
Or the polymorph D by described in any embodiment of the present invention is being prepared for preventing or treating mood disorders and delta opiate receptor
Purposes in the medicine of relevant disease.
Embodiment of the present invention provides (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- dimethyl piperazines simultaneously
Piperazine -1- bases) (3- hydroxy phenyls) methyl) phenyl) (4- methyl piperidine -1- bases) ketone and its pharmaceutically acceptable salt are (for example
Dihydrochloride) prepare for prevent or treat mood disorders or the disease relevant with delta opiate receptor medicine in purposes.
In some embodiments of the present invention, mood disorders disease is depression；The disease relevant with delta opiate receptor can
Think：Anxiety neurosis, pain, hypoxic-ischemic/reperfusion injury, colitis, alternatively ulcerative colitiss etc..
Embodiment of the present invention by room temperature slowly volatilize crystallization, suspend stirring, slow cooling, anti-solvent add, liquid-liquid
The methods such as gas-phase permeation, liquid-solid gas-phase permeation, high polymer induction crystallization prepare (4- ((R)-((2S, 5R) -4- (3- fluorine benzyls
Base)-(2,5- lupetazin -1- bases) (3- hydroxy phenyls) methyl) phenyl) (4- methyl piperidine -1- bases) ketone dihydrochloride
4 kinds of polymorph bs, E, H, D.4 kinds of polymorph dissolubility height, good absorbing, bioavailability height, small toxicity, the stability
It is good, depression and other potential diseases can be effectively prevented and treated, it is adapted to exploitation and the industrialized production of new drug.
After reading and understanding accompanying drawing and describing in detail, it can be appreciated that other aspects.
Description of the drawings
Accompanying drawing is the embodiment of the present invention to be further understood for providing, and constitutes a part for description, with
The specific embodiment in face is used to explain the embodiment of the present invention together, but does not constitute the restriction to the embodiment of the present invention.Attached
In figure：
Fig. 1 is (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyl)
Methyl) phenyl) (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph b XRPD figure；
Fig. 2 is (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyl)
Methyl) phenyl) (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph b TGA and DSC figure；
Fig. 3 is (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyl)
Methyl) phenyl) (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph E XRPD figure；
Fig. 4 is (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyl)
Methyl) phenyl) (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph E TGA and DSC figure.
Fig. 5 is (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyl)
Methyl) phenyl) (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph H XRPD figure；
Fig. 6 is (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyl)
Methyl) phenyl) (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph H TGA and DSC figure；
Fig. 7 is (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyl)
Methyl) phenyl) (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph D XRPD figure；
Fig. 8 is (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyl)
Methyl) phenyl) (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph D TGA and DSC figure；
Fig. 9 is the suspension and polymorph b -0.5%CMC-Na solution of free alkali -0.5%CMC-Na in rat plasma
In time dependent plasma concentration curve figure；
The cartogram that Figure 10 is that every group of rat is static in forced swim test, swims and climb the number of times that wallflow is.
Specific embodiment
The specific embodiment of the present invention is described in detail below.It should be appreciated that described herein concrete
Embodiment is merely to illustrate and explains the present invention, is not limited to the present invention.
The present invention is further illustrated 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 (PANalytical) Empyrean X
Gather on ray powder diffraction analysis instrument, XRPD parameters are as follows：
Thermogravimetry and differential scanning calorimetry
Thermogravimetry (TGA) collection of illustrative plates and differential scanning calorimetry (DSC) collection of illustrative plates of embodiment of the present invention is respectively in TA
Gather on Q500 thermogravimetric analyzers and TA Q200 differential scanning calorimeters, experiment parameter is as follows：
(4- ((R)-((2S, the 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy benzeness of embodiment 1
Base) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph b preparation
Take 10g (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyls)
Methyl) phenyl) to vial, the stirring of addition 200mL ethyl acetate is equal into vial for (4- methyl piperidine -1- bases) ketone
It is even, the 3.5mL concentrated hydrochloric acid that percent by volume is 37.5% is subsequently added, it is stirred at room temperature, to react 3 hours, vacuum drying is obtained final product
(4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyls) methyl) phenyl) (4-
Methyl piperidine -1- bases) ketone dihydrochloride polymorph b.
Prepare according to the method described above (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazins -
1- yls) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph b XRPD scheme such as
Shown in Fig. 1, its collection of illustrative plates peak information is shown in Table 1.The TGA and DSC of polymorph b schemes as shown in Fig. 2 as shown in Figure 2, polymorph
The fusing point of B is 171.6 DEG C (from DSC interpretations, its melting range is 154.4 DEG C -171.6 DEG C).
The XRPD collection of illustrative plates peak informations of the polymorph b of table 1
(4- ((R)-((2S, the 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy benzeness of embodiment 2
Base) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph E preparation
Weigh (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- of the embodiment 1 of 1.5g
Base) (3- hydroxy phenyls) methyl) phenyl) polymorph b of (4- methyl piperidine -1- bases) ketone dihydrochloride makees initial sample,
It is positioned over vial；It is positioned over this vial is open in the carboy equipped with 100mL acetonitriles or dichloromethane；Carboy
It is enclosed under room temperature condition and places 5 days, takes out solid, as polymorph E.
Prepare according to the method described above (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazins -
1- yls) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph E XRPD scheme such as
Shown in Fig. 3, its collection of illustrative plates peak information is shown in Table 2.The TGA and DSC of polymorph E schemes as shown in figure 4, as shown in Figure 4, polymorph
The fusing point of E is 170.4 DEG C (from DSC interpretations, its melting range is 161.1 DEG C -170.4 DEG C).
The XRPD collection of illustrative plates peak informations of the polymorph E of table 2
(4- ((R)-((2S, the 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy benzeness of embodiment 3
Base) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph H preparation
Weigh (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- of the embodiment 1 of 1.5g
Base) (3- hydroxy phenyls) methyl) phenyl) (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph b makees initial sample, plus
Enter 100mL dimethyl sulfoxide, be completely dissolved solid；Methyl iso-butyl ketone (MIBK) is slowly added dropwise to generating precipitation.By precipitate and separate, or
Sample is transferred under room temperature condition quick volatilization and obtains solid, as polymorph H.
Prepare according to the method described above (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazins -
1- yls) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph H XRPD scheme such as
Shown in Fig. 5, its collection of illustrative plates peak information is shown in Table 3.The TGA and DSC of polymorph H is schemed as shown in fig. 6, it will be appreciated from fig. 6 that polymorph
The fusing point of H is 172.0 DEG C (from DSC interpretations, its melting range is 166.8 DEG C -172.0 DEG C).
The XRPD collection of illustrative plates peak informations of the polymorph H of table 3
(4- ((R)-((2S, the 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy benzeness of embodiment 4
Base) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph H preparation
Weigh (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- of the embodiment 1 of 1.5g
Base) (3- hydroxy phenyls) methyl) phenyl) (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph b makees initial sample, puts
It is placed in vial；By the open big glass being positioned over equipped with 100mL1,4- dioxane or 2- methyltetrahydrofurans of this vial
In bottle；Carboy is enclosed under room temperature condition and places 5 days, takes out solid, as polymorph H.
Prepare according to the method described above (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazins -
1- yls) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph H XRPD figure,
TGA and DSC figures are identical with Fig. 5 and Fig. 6 respectively.
(4- ((R)-((2S, the 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy benzeness of embodiment 5
Base) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph H preparation
Weigh (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- of the embodiment 1 of 1.5g
Base) (3- hydroxy phenyls) methyl) phenyl) (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph b makees initial sample, puts
In being placed in open glass bottle；100mL Isosorbide-5-Nitraes-dioxane is added to obtain suspension, at ambient temperature magnetic agitation 4 days, from
The heart separates solid and is polymorph H.
Prepare according to the method described above (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazins -
1- yls) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph H XRPD figure,
TGA and DSC figures are identical with Fig. 5 and Fig. 6 respectively.
(4- ((R)-((2S, the 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy benzeness of embodiment 6
Base) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph H preparation
Weigh (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- of the embodiment 1 of 1.5g
Base) (3- hydroxy phenyls) methyl) phenyl) (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph b makees initial sample, puts
In being placed in open glass bottle；Add 30mL chloroforms and normal heptane mixed solvent (mixed proportion 1:9) suspension is obtained, in 50 DEG C of bars
Magnetic agitation 4 days under part, centrifugation solid is polymorph H.
Prepare according to the method described above (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazins -
1- yls) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph H XRPD figure,
TGA and DSC figures are identical with Fig. 5 and Fig. 6 respectively.
(4- ((R)-((2S, the 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy benzeness of embodiment 7
Base) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph D preparation
Weigh (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- of embodiment 10
Hydroxy phenyl) methyl) phenyl) (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph E makees initial sample, is heated to 100
DEG C, after 5 minutes, room temperature is naturally cooled under nitrogen protection and obtains polymorph D.
Prepare according to the method described above (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazins -
1- yls) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph D XRPD scheme such as
Shown in Fig. 7, its collection of illustrative plates peak information is shown in Table 4.The TGA and DSC of polymorph D schemes as shown in figure 8, as shown in Figure 8, polymorph
The fusing point of D is 178.1 DEG C (from DSC interpretations, its melting range is 171.8 DEG C -178.1 DEG C).
The XRPD collection of illustrative plates peak informations of the polymorph D of table 4
(4- ((R)-((2S, the 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy benzeness of embodiment 8
Base) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph D preparation
The present embodiment is different from embodiment 7 to be with reference to embodiment 7：The initial sample polymorph E of embodiment 7 is changed into work
The polymorph H of embodiment 2, other operations carry out (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- with embodiment 7
Lupetazin -1- bases) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph
The preparation of D.
Prepare according to the method described above (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazins -
1- yls) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph D XRPD figure,
TGA and DSC figures are identical with Fig. 7 and Fig. 8 respectively.
(4- ((R)-((2S, the 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy benzeness of embodiment 9
Base) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph D preparation
The present embodiment is different from embodiment 8 to be with reference to embodiment 8：The initial sample polymorph E of embodiment 8 is changed into work
The polymorph b of embodiment 1, other operations carry out (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- with embodiment 15
Lupetazin -1- bases) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph
The preparation of D.
Prepare according to the method described above (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazins -
1- yls) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph D XRPD figure,
TGA and DSC figures are identical with Fig. 7 and Fig. 8 respectively.
Test case
(4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy benzeness are determined respectively
Base) methyl) phenyl) (hereinafter referred to as free alkali, and using as tester, can for the free alkali of (4- methyl piperidine -1- bases) ketone
Prepared using existing conventional method) and the polymorph b of its dihydrochloride, E, H and D (hereinafter referred to as polymorph b, E, H
And D, be taken respectively from the sample of embodiment 1,2,3 and 7) dynamic solubility, bioavailability.
Dynamic solubility is tested
Free alkali, polymorph b, E, H and D are determined in water or Biomedia (simulated gastric fluid (SGF), simulation as fed
Intestinal juice (FeSSIF) or simulation fasting state intestinal juice (FaSSIF)) in dynamic solubility.
The preparation of simulated gastric fluid (SGF)
The Sodium Chloride of 0.2g and the triton x-100 of 0.1g are weighed into 100mL volumetric flasks, plus purification water dissolution, stirring
Add about 135uL concentrated hydrochloric acid (37%, 12M) after being completely dissolved to solid, then adjust pH with the hydrochloric acid of 1M or the sodium hydroxide of 1M
To 1.8.Purified water constant volume is finally used, simulated gastric fluid (SGF) is obtained, it is standby.
The preparation of simulation as fed intestinal juice (FeSSIF)
In taking glacial acetic acid, the sodium hydroxide of 0.20g, the Sodium Chloride of 0.59g to 50mL volumetric flasks of 0.41mL respectively, plus about
The purification water dissolution of 48mL, pH is adjusted to 5.0 with 1M hydrochloric acid or 1M sodium hydroxide, uses purified water constant volume.It is subsequently adding 0.56g's
(it is 4 by mol ratio to the powder of simulated intestinal fluid for simulated intestinal fluids, abbreviation SIF powder:1 Semen sojae atricolor
Lecithin and sodium taurocholate are constituted), simultaneously ultrasound is completely dissolved SIF powder for stirring, obtains simulation as fed intestinal juice
(FeSSIF) it is, standby.
The preparation of simulation 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, the Sodium Chloride of 0.31g
Into 50mL volumetric flasks, plus the purification water dissolution of about 48mL, pH to 6.5 is adjusted with the hydrochloric acid of 1M or the sodium hydroxide of 1M, with pure
Change water constant volume.The SIF powder of 0.11g is subsequently adding, simultaneously ultrasound is completely dissolved powder for stirring, obtains simulation fasting state intestinal juice
(FaSSIF) it is, standby.
Weigh free alkali, polymorph b, each 30mg of E, H and D respectively, add the purified water of 3mL, simulated gastric fluid (SGF),
Simulation as fed intestinal juice (FeSSIF) or simulation fasting state intestinal juice (FaSSIF)), shaken at room temperature, in the time point of setting
On, the suspension of 0.6mL is taken out every time, after being separated by filtration with 0.45 micron of nylon leaching film, solid sample carries out XRPD signs,
Concentration in clear liquid is measured with HPLC.Table 5 is shown in free alkali, polymorph b, the dynamic solubility of E, H and D, clear liquid
PH and by XRPD characterize not molten solid sample crystal formation.
PH in the free alkali of table 5, polymorph b, the dynamic solubility of E, H and D, clear liquid
Jing is tested, and as can be drawn from Table 5, compared with free alkali, is existed into hydrochloride polymorph thing B, E, H and the D after salt
Dissolubility in water, simulation as fed intestinal juice (FeSSIF) and simulation fasting state intestinal juice (FaSSIF) is significantly improved,
It is close to or slightly improves with the dissolubility of free alkali in simulated gastric fluid (SGF).
Bioavailability study
Using the blood drug level of drug target in the method detection SPF level SD rat plasmas of HPLC-MS/MS, and to rat
Respectively gavage gives the Relative biological of the suspension of free alkali -0.5%CMC-Na and the 0.5%CMC-Na solution of polymorph b
Availability is calculated and compared.
The preparation of the 0.5%CMC-Na suspensions of the drug target of free alkali group：Precision weighs free alkali 60.46mg and is placed in
In 15mL centrifuge tubes, 0.5%CMC-Na solution 12mL is measured into centrifuge tube, vortex 5min, ultrasonic 15min makes dispersion with graduated cylinder
Uniformly, obtain final product concentration be 5.04mg/ml free alkali 0.5%CMC-Na suspensions, it is now with the current and in administration process with
When shake.
The 0.5%CMC-Na solution of the drug target of polymorph b group is prepared：Precision weighs the polymorph b of 59.54mg
In being placed in 15mL centrifuge tubes, 0.5%CMC-Na solution 12mL is measured into centrifuge tube, vortex 5min, ultrasonic 15min makes with graduated cylinder
Be uniformly dispersed, obtain final product the 0.5%CMC-Na solution of the polymorph b of 4.96mg/mL, it is now with the current and in administration process at any time
Shaking.
From SPF levels SD rat 12, free alkali group, polymorph b group, 6 per group (male and female dual-purpose) are randomly divided into.It is dynamic
Water about 12h is can't help in thing fasting, weighs, and according to the weight of animals the administered volume of every rat is calculated, and makes dosage be 20mg/
kg.bw.During administration, difference gastric infusion, the 0.5%CMC-Na for extracting above two drug target respectively with 2mL syringes is mixed
Suspension, gastric perfusion needle is inserted in stomach from rat bicker and pushes solution.
Before administration (0h) and administration after 0.5,1,2,4,6,8,12 and 24h, take blood in rat eyeground vein clump
0.2mL, with 300IU/mL heparin (1：20) anticoagulant, is centrifuged (3000r/min) 15min.Surveyed with HPLC-MS/MS after separated plasma
Set the goal medicine blood drug level, and the blood concentration-time curve of acquisition is shown in Fig. 9.Two groups main is obtained with DAS2.0 computed in software
Medicine is shown in Table 6 for parameter.
The average medicine of the free alkali group of table 6 and polymorph b group for parameter (N=6)
The average AUC of free alkali group(0-24h)AFor 288.6ng/mL*h, the average AUC of polymorph b group(0-24h)DFor
517.5ng/mL*h, is calculated as follows relative bioavailability (F)：
I.e. under this experiment condition, polymorph b is 179% relative to the bioavailability of free alkali.Joined according to medicine generation
Digital display shows that polymorph b aqueous solution reaches peak faster, and average out to peak concentration is higher.
With reference to the bioavailability study of above-mentioned polymorph b, the bioavailability of polymorph D, E and H is carried out respectively
Test.It is different from the bioavailability study of polymorph b to be：To rat, respectively gavage gives polymorph D, E or H
0.5%CMC-Na solution, other operations are identical with above-mentioned bioavailability study.Resulting result and polymorph b
0.5%CMC-Na solution result is consistent, and polymorph D, E and H are relative to free alkali, and bioavailability is more preferable.
Polymorph b, E, H and D are improved compared with the dynamic solubility of free alkali, are more easy to pass through cell membrane in animal body,
It is more easy to be absorbed, so as to bioavailability is higher.
The forced swimming test of Application Example 1
Using forced swimming test, test polymorph b, the effect in terms of antidepressant effect of E, H and D.
(1) concrete experimental enviroment：Swimming test equipment is the clear glass circle cylinder that 46cm is high, interior diameter is 20cm, is tested
Water temperature is 23 DEG C～25 DEG C, and the test depth of water is 30cm, and per cylinder water only with once.
(2) preparation of concrete reagent
Vehicle controls liquid：0.9% normal saline.
Test the preparation of one group of experiment reagent：The polymorph b of 300mg is weighed with electronic balance, and using 0.9%
Normal saline dissolves to polymorph b, is finally settled to 100mL with 0.9% normal saline, now two in experiment reagent
The concentration of hydrochlorate is 3mg/mL, standby.
Test the preparation of two groups of experiment reagent：The polymorph b of 600mg is weighed with electronic balance, and using 0.9%
Normal saline dissolves to polymorph b, is finally settled to 100mL with 0.9% normal saline, now two in experiment reagent
The concentration of hydrochlorate is 6mg/mL, standby.
The preparation of positive control solution：The desipramine (DMI) of 400mg is weighed with electronic balance, with 0.9% normal saline
DMI is dissolved, subsequently 100mL is settled to 0.9% normal saline, it is standby.
(3) test method
Prepare SPF levels SD rat 40, be randomly divided into 4 groups, i.e. vehicle control group, positive controls, one group of experiment, experiment
Two groups, 10 per group.Test the previous day, rat is put into in water 15min to swim 15min in advance, to adapt to the environment of swimming test,
Subsequently take out and dry, be put in cage and put 15min under infrared lamp and place in former mouse cage.Formal swimming test is carried out after 24h, i.e.,
Rat is reentered in water after 24h, and Continuous Observation 5min, swimming process need to be imaged.It is administered during swimming twice.
(4) capacity and dosage, approach and cycle is administered
It is administered according to the administration capacity and approach shown in table 7.
The capacity (dosage) and approach of each group of table 7 administration
Positive controls containing DMI are administered three times, 23.5h, 5h and 1h abdominal cavity note 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 rat behavior for the video recording of process of the test.
Following three behaviors are recorded：
1) static-when rat floats on the water surface, not struggle, motion is then evaluated merely to keep its head to surface
Rat is static；
2) swim-have obvious swimming behavior and not just to keeping head to surface, or in circle cylinder medium ring
Trip, then evaluate rat for swimming；
3) climbing wall-rat fore paw has the behavior of the substantially turnover water surface, generally before circle casing wall, then evaluates rat to climb wall.
All behavior scorings are carried out by one, and for the skewed popularity for avoiding observing, scoring person is not only knowing about administrations
Under conditions of observed, score.Several test segments are randomly selected again, carry out the second wheel scoring to determine observation by scoring person
Accuracy.Test video recording is scored again to determine the accuracy between scoring person, second scoring by second scoring person
Person also requires that and observed in the case where administrations are not known about, finally in order to determine the effectiveness of method, by first scoring person again
Secondary scoring, and record the persistent period of various actions with stopwatch.
(6) statistical method
Variance analyses are carried out using SPSSwin11.0 softwares, variance adopts together one factor analysis of variance, heterogeneity of variance to adopt
Dunnett is checked.
(7) result of the test
According to the record result and statistical method of above-mentioned behavior scoring, tests below result is obtained.
8 every groups of rats of table are static, swim and climb the number of times that wallflow is
Note：Compared with vehicle control group：▲p<0.05,▲▲p<0.01,▲▲▲p<0.001。
The result of table 8 and Figure 10 shows：Give the sun that rat contains the positive control solution of 40mg/kg desipramines (DMI)
Property matched group can reduce the static number of times of rat, increase rats'swimming number of times, wall number of times is climbed in increase, compared with vehicle control group,
With significant difference (P<0.001, P<0.01, P<0.01)；Show that test method is feasible.Rat is given respectively contains 30mg/
Two groups of one group of the experiment and experiment of the experiment reagent of the polymorph b of kg and 60mg/kg can obviously reduce rat antidepressant effect
Static number of times, increases rats'swimming number of times, and wall number of times is climbed in increase, compared with vehicle control group, with significant difference (P<
0.001, P<0.01, P<0.01).
9 every groups of rats of table are static, swim and climb the persistent period that wallflow is
Note：Compared with vehicle control group：▲p<0.05,▲▲p<0.01,▲▲▲p<0.001。
The result of table 9 shows：Give the positive control that rat contains the positive control solution of 40mg/kg desipramines (DMI)
Group can reduce rat quiescent duration, increase the rats'swimming persistent period, and the wall persistent period is climbed in increase, with vehicle control group phase
Relatively, with significant difference (P<0.001, P<0.01, P<0.01)；Show that test method is feasible.Give rat respectively to contain
It is mandatory that two groups of one group of the experiment and experiment of the experiment reagent of the polymorph b of 30mg/kg and 60mg/kg can obviously reduce rat
Swimming quiescent duration, increases the rats'swimming persistent period, and the wall persistent period is climbed in increase, compared with vehicle control group, tool
There is significant difference (P<0.001, P<0.01, P<0.01).
Test shows that polymorph b has more preferable antidepressant effect.
With reference to the forced swimming test of above-mentioned polymorph b, the forced swimming test of polymorph E, H and D is carried out respectively.
It is different from the forced swimming test of polymorph b to be：Take polymorph D, E, H and replace polymorph b preparation experiment reagent, its
He operates identical with above-mentioned forced swimming test.Resulting result is consistent with polymorph b aqueous solution result, polymorph E,
H and D can effectively reduce the static times and duration of rat antidepressant effect, increase rats'swimming times and duration,
Wall times and duration is climbed in increase.
Present disclosure is the example of the principle of the embodiment of the present application, not the application is made any in form or substantive
On restriction, or the application is limited to into specific embodiment.It will be apparent to those skilled in the art that the application reality
Key element, compound, polymer, composition, compositionss, preparation, process of the technical scheme of example etc. are applied, can be changed,
Change, change, develop, without departing from embodiments herein as above, technical scheme, as defined in the claims
Principle, spirit and scope.These variations, the embodiment for changing, changing, develop 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 describe in detail herein be the present invention some embodiments.Additionally, the reality of the application
Apply some or all of arbitrarily possible combination of the example including various embodiments described herein, be also included within the application by
In the range of claim is defined.The patent quoted in this application or at any one, the patent application quoted or other references
Data in Anywhere mentioned all patents, patent application and other citations it is overall simultaneously with it accordingly by quoting
Enter.
Disclosure above is defined as illustrative rather than exhaustive.To those skilled in the art, this theory
The many changes of bright gathering of calligraphers hint and optional scheme.All these optional schemes and change are intended to be included in present claims
In the range of, wherein term " including " means " including, but are not limited to ".
Here completes the description to alternate embodiment of the present invention.One skilled in the art will recognize that this place
Other equivalent transformations for the embodiment stated, these equivalent transformations are also by included by investing the claims herein.
Industrial applicibility
(4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- that embodiment of the present invention is provided
Base) (3- hydroxy phenyls) methyl) phenyl) and (4- methyl piperidine -1- bases) ketone dihydrochloride 4 kinds of polymorph bs, E, H and D it is molten
Solution degree height, good absorbing, bioavailability height, small toxicity, good stability, can effectively prevent and treat depression and other
Potential disease, is adapted to exploitation and the industrialized production of new drug.Additionally, the system of 4 kinds of polymorphs of embodiment of the present invention offer
Preparation Method is simple, be adapted to industrialized production.
Claims (27)
1. (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyls) methyl) benzene
Base) (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph b, the X-ray powder diffraction figure bag of the polymorph b
Include the following diffraction maximum at 2 θ values：17.6 ± 0.2,8.0 ± 0.2,23.6 ± 0.2,13.0 ± 0.2 and 9.2 ± 0.2
º。
2. polymorph b as claimed in claim 1, wherein, the X-ray powder diffraction figure of the polymorph b is additionally included in
Diffraction maximum at following any one or more 2 θ values：19.8±0.2º、15.6±0.2º、14.6±0.2º、
25.4 ± 0.2,11.7 ± 0.2,26.7 ± 0.2,19.4 ± 0.2,22.5 ± 0.2,16.8 ± 0.2 and 18.4 ± 0.2
º。
3. polymorph b as claimed in claim 1, wherein, the polymorph b using differential scanning calorimetry determine it is molten
O'clock in the range of 154.4 C-171.6 C, alternatively, about 171.6 C.
4. the polymorph b as any one of claim 1-3, wherein, the polymorph b has shown in accompanying drawing 1
XRPD schemes, and the TGA shown in accompanying drawing 2 and DSC figures.
5. (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyls) methyl) benzene
Base) preparation method of polymorph b of (4- methyl piperidine -1- bases) ketone dihydrochloride is：
To (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyls) methyl) benzene
Base) organic solvent is added in (4- methyl piperidine -1- bases) ketone, concentrated hydrochloric acid solution is subsequently added, stirring is until no longer separate out solid
Body, filters, and is dried, and obtains the polymorph b,
Wherein, solvent is selected from group consisting of in the preparation method：Acetone, methyl iso-butyl ketone (MIBK), methyl isopropyl ketone, ring
Hexane, hexahydrotoluene, normal hexane, petroleum ether, ether, methyl tertiary butyl ether(MTBE), 1,4- dioxane, methyl ethyl ketone, methyl
In isobutyl ketone, methyl pyrrolidone any one or it is more kinds of, or ethyl acetate, butyl acetate, Ethyl formate, acetic acid is different
In butyl ester, isopropyl acetate, methyl acetate, propyl acetate any one or it is more kinds of.
6. in preparation method as claimed in claim 5, relative to (4- ((R)-((2S, 5R) -4- (3- fluorine benzyls described in 10g
Base)-(2,5- lupetazin -1- bases) (3- hydroxy phenyls) methyl) phenyl) (4- methyl piperidine -1- bases) ketone, added
The amount of organic solvent is 50mL-1000mL, is optionally 50mL-300mL, and the amount of the concentrated hydrochloric acid for being added is 1.5mL-7.0mL,
It is optionally 1.75mL -5.25mL；The time of the stirring reaction is 0.5h-12h, is optionally 2h-4h；Reaction temperature is
10ºC-40ºC。
7. (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyls) methyl) benzene
Base) (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph E, the X-ray powder diffraction figure bag of the polymorph E
Include the following diffraction maximum at 2 θ values：14.8 ± 0.2,12.7 ± 0.2,8.2 ± 0.2,18.2 ± 0.2 and 13.1 ± 0.2
º。
8. polymorph E as claimed in claim 7, wherein, the X-ray powder diffraction figure of the polymorph E is additionally included in
Diffraction maximum at following any one or more 2 θ values：26.6±0.2º、15.1±0.2º、25.3±0.2º、
13.3±0.2º、23.6±0.2º、21.9±0.2º、11.7±0.2º、9.2±0.2º、19.2±0.2º、27.3±0.2º、
16.3 ± 0.2,20.8 ± 0.2,27.9 ± 0.2,29.4 ± 0.2 and 21.3 ± 0.2.
9. polymorph E as claimed in claim 7, wherein, the polymorph E using differential scanning calorimetry determine it is molten
O'clock in the range of 161.1 C-170.4 C, it is preferable that about 170.4 C.
10. polymorph E as claimed in any one of claims 7-9, wherein, the polymorph E has shown in accompanying drawing 3
XRPD schemes, and the TGA shown in accompanying drawing 4 and DSC figures.
11. (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyls) methyl) benzene
Base) preparation method of polymorph E of (4- methyl piperidine -1- bases) ketone dihydrochloride is：
By the polymorph b as described in any one of claim 1-4, vial is positioned over；Dress is positioned over by this vial is open
In having the carboy of solvent；Place 5 days under the conditions of the closed room temperature of carboy, taking-up solid, as polymorph E,
Wherein, in preparation method, the solvent is selected from group consisting of：Acetonitrile, dimethylformamide, diethyl acetyl
In amine, Methanamide, dichloromethane, dimethyl sulfoxide, tetrahydrofuran any one or it is more kinds of.
12. (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyls) methyl) benzene
Base) (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph H, the X-ray powder diffraction figure bag of the polymorph H
Include the diffraction maximum at following 2 θ values：12.9 ± 0.2,8.0 ± 0.2,17.6 ± 0.2,23.4 ± 0.2 and 14.5 ± 0.2.
13. polymorph H as claimed in claim 12, wherein, the X-ray powder diffraction figure of the polymorph H also includes
In the diffraction maximum at following any one or more 2 θ values：9.1±0.2º、25.3±0.2º、16.8±0.2º、
26.5±0.2º、19.5±0.2º、11.6±0.2º、22.5±0.2º、15.4±0.2º、13.3±0.2º、19.8±0.2º、
22.0 ± 0.2,26.1 ± 0.2 and 27.4 ± 0.2.
14. polymorph H as claimed in claim 12, wherein, the polymorph H is determined using differential scanning calorimetry
Fusing point is in the range of 166.8 C-172.0 C, it is preferable that about 172.0 C.
The 15. polymorph H as any one of claim 12-14, wherein, the polymorph H has shown in accompanying drawing 5
XRPD figure, and the TGA shown in accompanying drawing 6 and DSC figure.
16. (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyls) methyl) benzene
Base) (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph H preparation method, including：
(1) to the polymorph b as described in any one of claim 1-4, solvent is added to be completely dissolved solid；It is slowly added dropwise
Methyl iso-butyl ketone (MIBK) to precipitation is generated, by precipitate and separate, as polymorph H；Or
(2) polymorph b as described in any one of claim 1-4 is positioned over into vial；It is positioned over this vial is open
In carboy equipped with solvent；After carboy is placed in confined conditions, solid, as polymorph H are taken out；Or
(3) polymorph b as described in any one of claim 1-4 is positioned in the open glass bottle equipped with solvent；Obtain
Suspension, after stirring under certain room temperature condition, centrifugation solid is polymorph H；Or
(4) polymorph b as described in any one of claim 1-4 is positioned in open glass bottle；Add chloroform and positive heptan
Alkane mixed solvent（Mixed proportion 1:9）Suspension is obtained, after stirring under the conditions of uniform temperature, centrifugation solid is polycrystalline
Type thing H,
Wherein, in preparation method (1), the solvent is selected from group consisting of：Acetonitrile, dimethylformamide, diethyl
In acetamide, Methanamide, dichloromethane, dimethyl sulfoxide, tetrahydrofuran any one or it is more kinds of；In method (2)-(3), institute
Solvent is stated selected from addition 2- methyltetrahydrofurans or 1,4- dioxane or dichloromethane or ethanol and toluene Mixed Solvent（Mixing
Ratio 1:9）Or chloroform and normal heptane mixed solvent（Mixed proportion 1:9）.
17. preparation methoies as claimed in claim 16, wherein, in method (1)-(4), relative to 1.5g polymorph bs, institute
The amount of the solvent for adding is 50mL-1000mL, is chosen as 50mL-300mL；Separately, it is temperature required in method (2)-(4)
For 10 C -80 C, preferably 25 C or 50 C, mixing time is -10 days 1 day, is optionally 4 days；In method (3)
It is described to place -7 days 1 day under the conditions of closed room temperature, it is optionally 5 days；In method (4), described standing is -7 days 1 day, can
Selection of land is 3 days.
18. (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyls) methyl) benzene
Base) (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph D, the X-ray powder diffraction figure bag of the polymorph D
Include the following diffraction maximum at 2 θ values：17.7 ± 0.2,20.1 ± 0.2,13.0 ± 0.2,8.9 ± 0.2 and 16.2 ± 0.2
º。
19. polymorph D as claimed in claim 18, wherein, the X-ray powder diffraction figure of the polymorph D also includes
In the diffraction maximum at following any one or more 2 θ values：7.8±0.2º、15.7±0.2º、22.4±0.2º、
19.5 ± 0.2,25.4 ± 0.2,29.0 ± 0.2,31.7 ± 0.2 and 14.8 ± 0.2.
20. polymorph D as claimed in claim 18, wherein, the polymorph D is determined using differential scanning calorimetry
Fusing point is in the range of 171.8 C-178.1 C, it is preferable that about 178.1 C.
The 21. polymorph D as any one of claim 18-20, wherein, the polymorph D has shown in accompanying drawing 7
XRPD figure, and the TGA shown in accompanying drawing 8 and DSC figure.
22. (4- ((R)-((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyls) methyl) benzene
Base) (4- methyl piperidine -1- bases) ketone dihydrochloride polymorph D preparation method, including：
(1) by 100mg 4- ((α R)-α-((2S, 5R) -4- (3- luorobenzyls) -2,5- dimethyl -1- piperazinyls)-(3- hydroxyls
Benzyl))-(4- methyl isophthalic acids-piperidyl)-ketone be added in organic solvent mix；After add concentrated hydrochloric acid（37.5%）, stirring is instead
Ying Hou, vacuum drying, obtains final product polymorph D；Or
(2) by the polymorph E as described in any one of claim 7-11,100 DEG C are heated to, it is naturally cold under nitrogen protection
But polymorph D is obtained to room temperature；Or
(3) by the polymorph H as described in any one of claim 12-16,100 DEG C are heated to, it is naturally cold under nitrogen protection
But polymorph D is obtained to room temperature；Or
(4) by the polymorph b as described in any one of claim 1-4,100 DEG C are heated to, under nitrogen protection natural cooling
Polymorph D is obtained to room temperature,
Wherein in preparation method (1), the organic solvent is selected from：Acetone, methyl iso-butyl ketone (MIBK), methyl isopropyl ketone, hexamethylene,
Hexahydrotoluene, normal hexane, petroleum ether, ether, methyl tertiary butyl ether(MTBE), 1,4- dioxane, methyl ethyl ketone, methyl-isobutyl
In ketone, methyl pyrrolidone any one or it is more kinds of.
23. preparation methoies as claimed in claim 22, wherein, in method (1), relative to described in 100mg (4- ((R)-
((2S, 5R) -4- (3- luorobenzyls)-(2,5- lupetazin -1- bases) (3- hydroxy phenyls) methyl) phenyl) (4- methyl piperidines -
1- yls) ketone, the amount of the organic solvent for being added is 0.5mL-10mL, is optionally 0.5mL-3mL, the concentrated hydrochloric acid for being added
Measure as 10mL-100mL, be optionally 30mL -40mL；The time of the stirring reaction is 0.5h-12h, is optionally 2h-4h；
Reaction temperature is 10 C-40 C.
24. a kind of pharmaceutical compositions, comprising the polymorph b as any one of claim 1-4 or by such as claim
The polymorph b that preparation method any one of 5-6 is obtained, the polymorph E as described in any one of claim 7-10
Or obtained by preparation method as described in any of claims 11 polymorph E, such as any one of claim 12-15 institute
The polymorph H for the stating or polymorph H obtained by the preparation method as any one of claim 16-17, such as right
Require the polymorph D described in any one of 18-21 or obtained by the preparation method as any one of claim 22-23
At least one in polymorph D.
25. pharmaceutical compositions as claimed in claim 24, also including pharmaceutically acceptable carrier or excipient.
26. a kind of pharmaceutical compositions, comprising the polymorph b as any one of claim 1-4 or by such as claim
The polymorph b that preparation method any one of 5-6 is obtained, the polymorph E as described in any one of claim 7-10
Or obtained by preparation method as described in any of claims 11 polymorph E, such as any one of claim 12-15 institute
The polymorph H for the stating or polymorph H obtained by the preparation method as any one of claim 16-17, such as right
Require the polymorph D described in any one of 18-21 or obtained by the preparation method as any one of claim 22-23
Purposes of the polymorph D in the medicine for preventing or treating the mood disorders disease relevant with delta opiate receptor is prepared.
27. purposes as claimed in claim 26, wherein the mood disorders disease is depression.
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| CN107157945A (en) * | 2017-06-02 | 2017-09-15 | 云南省药物研究所 | A kind of tablet of new opioid activator hydrochloride and preparation method thereof |
| WO2018090360A1 (en) * | 2016-11-21 | 2018-05-24 | 云南省药物研究所 | Polymorph of triaryldimethylpiperazine dihydrochloride and preparation method and application thereof |
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| WO2006113468A2 (en) * | 2005-04-14 | 2006-10-26 | Mount Cook Biosciences, Inc. | Compositions of novel opioid compounds and method of use thereof |
| CN101318952A (en) * | 2008-06-04 | 2008-12-10 | 昆明贝尔吉科技有限公司 | Sigma Acceptor activator compound and uses thereof |
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| WO2006113468A2 (en) * | 2005-04-14 | 2006-10-26 | Mount Cook Biosciences, Inc. | Compositions of novel opioid compounds and method of use thereof |
| CN101318952A (en) * | 2008-06-04 | 2008-12-10 | 昆明贝尔吉科技有限公司 | Sigma Acceptor activator compound and uses thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018090360A1 (en) * | 2016-11-21 | 2018-05-24 | 云南省药物研究所 | Polymorph of triaryldimethylpiperazine dihydrochloride and preparation method and application thereof |
| US10730851B2 (en) | 2016-11-21 | 2020-08-04 | Yunnan Institute Of Materia Medica | Polymorph of triaryldimethylpiperazine dihydrochloride and preparation method and application thereof |
| CN107157945A (en) * | 2017-06-02 | 2017-09-15 | 云南省药物研究所 | A kind of tablet of new opioid activator hydrochloride and preparation method thereof |
| CN107157945B (en) * | 2017-06-02 | 2021-03-12 | 云南省药物研究所 | Novel opium delta receptor stimulant hydrochloride tablet and preparation method thereof |
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