CN104119298B - Hydrobromic acid Wo Saiting or hydrobromic acid are fertile for Xi Ting - Google Patents
Hydrobromic acid Wo Saiting or hydrobromic acid are fertile for Xi Ting Download PDFInfo
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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Abstract
The present invention relates to hydrobromic acid Wo Saiting or hydrobromic acid is fertile for Xi Ting.Specifically, the present invention relates to 1 [2 (2,4 3,5-dimethylphenyl sulfenyls) phenyl] crystallization of piperazine hydrobromide, it uses Cu K α radiation, in the powder X-ray x ray diffraction collection of illustrative plates represented with 2 θ angles, at about 6.89 °, about 9.73 °, about 13.78 ° and about 14.62 °, there is diffraction maximum.The invention still further relates to the preparation method of this crystallization, and comprise their pharmaceutical composition.The compounds of this invention shows the inhibitory activity of serotonin reabsorption and to serotonin receptor 1A (5 HT1A) and serotonin receptor 3 (5 HT3) active, and this compound may be used for treating the relevant disease of CNS, specifically can be used for treating depression particularly severe adult's depression.Can be additionally used in and treat the relevant disease of other CNS.
Description
Technical field
The present invention relates to a kind of compound, this compound shows the inhibitory activity of serotonin reabsorption and to thrombocytin
Acceptor 1A (5-HT1A) and serotonin receptor 3 (5-HT3) active, and this compound may be used for treating the relevant disease of CNS
Sick.More particularly it relates to an the inhibitor of serotonin transporter, it is that one can be used for treating depression spy
It not the medicine of severe adult's depression, particularly relate to a kind of chemical name and can be described as 1-[2-(2,4-3,5-dimethylphenyl sulfenyl)
Phenyl] medicine of piperazine hydrobromide, relate more particularly to the crystallization of this medicine.This 1-[2-(2,4-3,5-dimethylphenyl sulfenyl)
Phenyl] piperazine hydrobromide has a following chemical constitution:
Background technology
Selective serotonin reuptake inhibithors (SSRI) has been (special for treating some CNS relevant disease for many years
Depressed, anxiety and social phobia) the first selection therapy, this is because (that is, traditional with the compound used before
Tricyclic compound) compare, these inhibitor be effective, tolerance is good and has favourable security.
But, use SSRI to carry out curative treatment and hindered by substantial amounts of non-response person, described non-response person
It is and SSRI treatment is not produced response or SSRI is treated the patient of the response only producing limited extent.Additionally, generally, SSRI
Treat and just start to demonstrate effect after treating several weeks.
In order to avoid these shortcomings of SSRI treatment, psychiatrist uses strengthening strategy sometimes.Such as, all by combining
Such as the mood stabilizer of lithium carbonate or triiodide thyroxine etc or strengthen antidepression by parallel employing electroshock
The effect of agent.
It is known that suppression serotonin transporter (SERT) and to active this of one or more serotonin receptors
It is favourable for planting combination.Have been found that serotonin reabsorption inhibitor before and there is 5-HT2CAntagonism or the most exciting work
With (compound is to 5-HT2CAcceptor has negative effect) compound combine the water of the 5-HT (thrombocytin) that can make in final area
Put down and be greatly improved, as measure in microdialysis experiments (seeing patent document WO01/41701).This clinically may
Mean the onset of antidepressant effect faster, and might mean that the therapeutic action of serum reuptake inhibithors (SRI) obtains
With strengthening or enhancing.
It is similar to, it has been reported that (it is a kind of 5-HT to pindolol1APartial agonist) with serotonin reabsorption inhibitor phase
In conjunction with meeting quick acting [Psych.Res., 125,81-86,2004].
Such as the CNS relevant disease of depressed, anxiety and schizophrenia etc often with such as cognitive disorder or damage it
The disorder of class or dysfunction and deposit generation [Scand.J.Psych., 43,239-251,2002；Am.J.Psych, 158,
1722-1725,2001].
Speculate and have multiple neurotransmitters relevant with the neuron event of regulation cognitive process.Specifically, cholinergic body
Tying up to play an important role in cognitive process, the compound therefore affecting cholinergic system can be potentially served as treating cognitive damage
Wound.It is known that affect 5-HT1AAcceptor and/or 5-HT3The compound of acceptor also have impact on cholinergic system, and these compounds
Can be used for treating cognitive impairment with former state.
Thus, it is expected that play 5-HT1AAnd/or 5-HT3The compound of receptor active can be used for treating cognitive impairment.Additionally
The compound playing SERT activation can be particularly useful for the treatment of the cognitive impairment of patients with depression, this is because this compound
Additionally provide the quick acting effect for the treatment of depression.
WO2003/029232 (or CN1561336A, Chinese Patent Application No. 02819025.4) discloses such as compound
1-[2-(2,4-3,5-dimethylphenyls-sulfanyl) phenyl] piperazine (i.e. described in embodiment 1e in this patent document, this kind of free alkali
The compound of form can be described as Wo Saiting or fertile for Xi Ting in the present invention, and the English name of this kind of free alkali form compound leads to
It is frequently referred to Vortioxetine) as the compound with SERT activation.
Additionally, CN101472906A (Chinese Patent Application No. 200780022338.5) discloses the hydrobromic acid of Wo Saiting
Salt, the solvate such as hydrate of this hydrobromate and other acid-addition salts, particularly, in this CN101472906A also
Disclose the α type crystallization of the multiple crystal formation of hydrobromic acid Wo Saiting, such as hydrobromic acid Wo Saiting, the crystallization of β type, the crystallization of γ type, and
It is believed that the β type crystallization of hydrobromic acid Wo Saiting has good pharmaceutical properties.
But, this area still expects there is new medicine to treat depression particularly severe adult's depression, expects this
Plant medicine and there is useful pharmaceutical properties.
Summary of the invention
The purpose of this invention is to provide a kind of 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine hydrobromide,
Particularly its crystal form, expects that this medicine has at least one useful pharmaceutical properties as described in the present invention.Go out people's will
Material ground finds have 1-[2-(2, the 4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine hydrobromide of the crystal form of feature of present invention
Present useful pharmaceutical properties.The present invention finds based on this and is accomplished.
To this end, first aspect present invention provides the crystallization with compounds of Formula I
The crystallization of any embodiment according to a first aspect of the present invention, wherein said compound of formula I is 1-[2-(2,4-
3,5-dimethylphenyl sulfenyl) phenyl] piperazine hydrobromide.Molecular formula C18H22N2S of this hydrobromic acid addition salt, HBr, molecular weight
379.36；Molecular formula C18H22N2S of free alkali, molecular weight 298.45.
The crystallization of any embodiment according to a first aspect of the present invention, wherein said compound of formula I is the fertile match of hydrobromic acid
Spit of fland.
The crystallization of any embodiment according to a first aspect of the present invention, wherein said compound of formula I is that hydrobromic acid is fertile to be replaced
Xi Ting.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, at about 6.89 °, about 9.73 °, about 13.78 ° and about 14.62 °, there is diffraction maximum.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, have at 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 ° and 14.62 ± 0.12 °
Diffraction maximum.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, salt free ligands peak at 17.25 ± 0.12 °.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, salt free ligands peak at 17.65 ± 0.12 °.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 °.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, at 16.90 ± 0.12 °, there is diffraction maximum.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, at 17.40 ± 0.12 °, there is diffraction maximum.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, at 16.90 ± 0.12 ° and 17.40 ± 0.12 °, there is diffraction maximum.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 °,
Diffraction maximum is had at 16.90 ± 0.12 °.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 °,
Diffraction maximum is had at 17.40 ± 0.12 °.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 °,
16.90 ± 0.12 °, have diffraction maximum at 17.40 ± 0.12 °.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 °,
16.90 ± 0.12 °, have diffraction maximum, and salt free ligands at 17.25 ± 0.12 ° and 17.65 ± 0.12 ° at 17.40 ± 0.12 °
Peak.
Although have been found that the present invention crystallization β type contained with in CN101472906B as crystallizing 6.89 ±
0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, show diffraction maximum at 14.62 ± 0.12 °, but completely unexpected,
Two peaks between 16.5 °～18.0 ° are the most significantly different, for two diffraction maximums that the crystallization of β type is distinguished at this, this
The angle of diffraction at two peaks that the crystallization of bright Type B is distinguished at this all diminishes.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 13.22 ± 0.12 °, 13.78
±0.12°、14.62±0.12°、16.12±0.12°、16.90±0.12°、17.40±0.12°、18.62±0.12°、
18.95 ± 0.12 °, 19.46 ± 0.12 °, 20.65 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 13.22 ± 0.12 °, 13.78
±0.12°、14.62±0.12°、16.12±0.12°、16.90±0.12°、17.40±0.12°、18.62±0.12°、
18.95 ± 0.12 °, 19.46 ± 0.12 °, 20.65 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °, and 17.25 ±
Salt free ligands peak at 0.12 ° and 17.65 ± 0.12 °.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22
±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、
17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±
0.12 °, 21.89 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22
±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、
17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±
0.12 °, 21.89 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °, and at 17.25 ± 0.12 ° and 17.65 ± 0.12 °
Salt free ligands peak.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22
±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、
17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±
0.12°、21.89±0.12°、22.68±0.12°、24.35±0.12°、25.38±0.12°、28.12±0.12°、28.49
± 0.12 °, have diffraction maximum at 29.37 ± 0.12 °.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22
±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、
17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±
0.12°、21.89±0.12°、22.68±0.12°、24.35±0.12°、25.38±0.12°、28.12±0.12°、28.49
± 0.12 °, have diffraction maximum, and salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 ° at 29.37 ± 0.12 °.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, has substantially as shown in Figure 1
Shown powder x-ray diffraction collection of illustrative plates.
The crystallization of any embodiment according to a first aspect of the present invention, it uses Cu-K α radiation, has substantially as shown in Figure 1
Shown powder x-ray diffraction collection of illustrative plates, and salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 °.
Further, second aspect present invention provides the crystallization with compounds of Formula I
The crystallization of any embodiment according to a second aspect of the present invention, it is little that it places 5 under the relative humidity conditions of 90%
Time, the amount absorbing water is less than 1%, preferably smaller than 0.75%, preferably smaller than 0.5%.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, at about 6.89 °, about 9.73 °, about 13.78 ° and about 14.62 °, there is diffraction maximum.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, have at 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 ° and 14.62 ± 0.12 °
Diffraction maximum.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, salt free ligands peak at 17.25 ± 0.12 °.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, salt free ligands peak at 17.65 ± 0.12 °.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 °.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, at 16.90 ± 0.12 °, there is diffraction maximum.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, at 17.40 ± 0.12 °, there is diffraction maximum.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, at 16.90 ± 0.12 ° and 17.40 ± 0.12 °, there is diffraction maximum.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 °,
Diffraction maximum is had at 16.90 ± 0.12 °.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 °,
Diffraction maximum is had at 17.40 ± 0.12 °.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 °,
16.90 ± 0.12 °, have diffraction maximum at 17.40 ± 0.12 °.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 °,
16.90 ± 0.12 °, have diffraction maximum, and salt free ligands at 17.25 ± 0.12 ° and 17.65 ± 0.12 ° at 17.40 ± 0.12 °
Peak.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 13.22 ± 0.12 °, 13.78
±0.12°、14.62±0.12°、16.12±0.12°、16.90±0.12°、17.40±0.12°、18.62±0.12°、
18.95 ± 0.12 °, 19.46 ± 0.12 °, 20.65 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 13.22 ± 0.12 °, 13.78
±0.12°、14.62±0.12°、16.12±0.12°、16.90±0.12°、17.40±0.12°、18.62±0.12°、
18.95 ± 0.12 °, 19.46 ± 0.12 °, 20.65 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °, and 17.25 ±
Salt free ligands peak at 0.12 ° and 17.65 ± 0.12 °.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22
±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、
17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±
0.12 °, 21.89 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22
±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、
17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±
0.12 °, 21.89 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °, and at 17.25 ± 0.12 ° and 17.65 ± 0.12 °
Salt free ligands peak.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22
±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、
17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±
0.12°、21.89±0.12°、22.68±0.12°、24.35±0.12°、25.38±0.12°、28.12±0.12°、28.49
± 0.12 °, have diffraction maximum at 29.37 ± 0.12 °.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22
±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、
17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±
0.12°、21.89±0.12°、22.68±0.12°、24.35±0.12°、25.38±0.12°、28.12±0.12°、28.49
± 0.12 °, have diffraction maximum, and salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 ° at 29.37 ± 0.12 °.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, has substantially as shown in Figure 1
Shown powder x-ray diffraction collection of illustrative plates.
The crystallization of any embodiment according to a second aspect of the present invention, it uses Cu-K α radiation, has substantially as shown in Figure 1
Shown powder x-ray diffraction collection of illustrative plates, and salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 °.
Further, third aspect present invention provides the crystallization with compounds of Formula I
The crystallization of any embodiment according to a third aspect of the present invention, when it reaches saturated in the water of 25 ± 1 DEG C, this is saturated
The concentration of solution compounds of formula I is more than 4mg/ml more than 2mg/ml, such as concentration more than 3mg/ml, such as concentration, the denseest
Degree more than 5mg/ml, such as its concentration be 2～10mg/ml, such as its concentration is 3～10mg/ml, such as its concentration be 4～
10mg/ml, such as its concentration are 5～10mg/ml.Above-mentioned concentration is that those skilled in the art easily measure, and such as, makes appropriate
The present invention crystallization of (exceeding saturation capacity) is placed in the water of a certain amount of 25 ± 1 DEG C, after being sufficiently stirred for, stands 24 at this temperature
Hour, centrifugal, draw middle settled solution, re-use suitable method and measure the concentration of the compound of formula I in this solution, i.e.
?.In the present invention, this concentration is also referred to as surveyed material solubility in 25 ± 1 DEG C of water.
The method of the concentration of the compound of formula I in said determination solution, such as, can use HPLC method.Referring for example to
It HPLC method described in [0044] section of CN102317272A i.e. Chinese Patent Application No. 201080007947.5 specification.At this
In invention, if not otherwise indicated, when measuring amount or its purity of compound of formula I in various sample, be all use above-mentioned
The method of CN102317272A is carried out.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, at about 6.89 °, about 9.73 °, about 13.78 ° and about 14.62 °, there is diffraction maximum.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, have at 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 ° and 14.62 ± 0.12 °
Diffraction maximum.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, salt free ligands peak at 17.25 ± 0.12 °.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, salt free ligands peak at 17.65 ± 0.12 °.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 °.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, at 16.90 ± 0.12 °, there is diffraction maximum.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, at 17.40 ± 0.12 °, there is diffraction maximum.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, at 16.90 ± 0.12 ° and 17.40 ± 0.12 °, there is diffraction maximum.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 °,
Diffraction maximum is had at 16.90 ± 0.12 °.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 °,
Diffraction maximum is had at 17.40 ± 0.12 °.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 °,
16.90 ± 0.12 °, have diffraction maximum at 17.40 ± 0.12 °.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 °,
16.90 ± 0.12 °, have diffraction maximum, and salt free ligands at 17.25 ± 0.12 ° and 17.65 ± 0.12 ° at 17.40 ± 0.12 °
Peak.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 13.22 ± 0.12 °, 13.78
±0.12°、14.62±0.12°、16.12±0.12°、16.90±0.12°、17.40±0.12°、18.62±0.12°、
18.95 ± 0.12 °, 19.46 ± 0.12 °, 20.65 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 13.22 ± 0.12 °, 13.78
±0.12°、14.62±0.12°、16.12±0.12°、16.90±0.12°、17.40±0.12°、18.62±0.12°、
18.95 ± 0.12 °, 19.46 ± 0.12 °, 20.65 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °, and 17.25 ±
Salt free ligands peak at 0.12 ° and 17.65 ± 0.12 °.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22
±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、
17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±
0.12 °, 21.89 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22
±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、
17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±
0.12 °, 21.89 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °, and at 17.25 ± 0.12 ° and 17.65 ± 0.12 °
Salt free ligands peak.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22
±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、
17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±
0.12°、21.89±0.12°、22.68±0.12°、24.35±0.12°、25.38±0.12°、28.12±0.12°、28.49
± 0.12 °, have diffraction maximum at 29.37 ± 0.12 °.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22
±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、
17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±
0.12°、21.89±0.12°、22.68±0.12°、24.35±0.12°、25.38±0.12°、28.12±0.12°、28.49
± 0.12 °, have diffraction maximum, and salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 ° at 29.37 ± 0.12 °.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, has substantially as shown in Figure 1
Shown powder x-ray diffraction collection of illustrative plates.
The crystallization of any embodiment according to a third aspect of the present invention, it uses Cu-K α radiation, has substantially as shown in Figure 1
Shown powder x-ray diffraction collection of illustrative plates, and salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 °.
Further, fourth aspect present invention provides the crystallization with compounds of Formula I
The crystallization of any embodiment according to a fourth aspect of the present invention, during its size-reduced one-tenth fine powder, this fine powder is crisp
After broken degree somascope disposes 5 minutes with the rotational speed of every point of kind 25 ± 1 turns, remaining at the powder of friability somascope inwall
Amount (%) is less than 2%, e.g., less than 1.5%, e.g., less than 1%, e.g., less than 0.75%, e.g., less than 0.5%.
Above-mentioned term " fine powder " is to well known to a person skilled in the art, such as determined in two notes on the use of 2010 version pharmacopeia
Justice, can be all by No. six sieves and containing sieving the powder no less than 95% by No. seven.The sieves such as No. six sieves and No. seven sieves
Definition also can be found in this pharmacopoeial definitions.Above-mentioned term " friability somascope " is to well known to a person skilled in the art, such as
Defined in two annex XG of version pharmacopeia in 2010, in the present invention, if not otherwise indicated, friability somascope is all such as this
Described by pharmacopeia.Powder residual volume (%) reflects the powder adhesion at friability somascope inwall, although this phenomenon is still
Explained without any definite theory, but this sticking to largely may be relevant with the antistatic property of powder, and
This performance will affect the pulverizing of pharmaceutical technology, such as bulk drug, preparation processing etc..Generally speaking powder residual volume (%) is little
It is preferred in 1%, and when more than 1%, pharmacy procedure can be had adverse effect on.The mensuration of conducting powder end residual volume
Time, the addition of medicinal powder can be generally 10g.Its mensuration process is simple, and those skilled in the art easily operate.Example
As, a kind of typical mensuration process is as follows: learns from else's experience and is ground into the powder about 10g of fine powder, accurately weighed, is placed in friability inspection
Instrument, after disposing 5 minutes with the rotational speed of every point of kind 25 ± 1 turns, is poured into powder in the most accurately weighed pan paper, should
Pan paper and powder precise weighing in the lump, calculates the powder remaining in friability somascope inwall, and it is remaining to calculate powder accordingly
Amount (%), i.e.=[(amount of powder in addition-pan paper) ÷ addition] × 100%.It addition, the present inventor uses stainless steel
The friability somascope (its size is still identical with the friability somascope of above-mentioned pharmacopeia) of material measures, and finds that identical material makes
Essentially identical with the powder residual volume (%) measured by the friability somascope of unlike material.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, at about 6.89 °, about 9.73 °, about 13.78 ° and about 14.62 °, there is diffraction maximum.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, have at 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 ° and 14.62 ± 0.12 °
Diffraction maximum.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, salt free ligands peak at 17.25 ± 0.12 °.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, salt free ligands peak at 17.65 ± 0.12 °.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 °.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, at 16.90 ± 0.12 °, there is diffraction maximum.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, at 17.40 ± 0.12 °, there is diffraction maximum.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, at 16.90 ± 0.12 ° and 17.40 ± 0.12 °, there is diffraction maximum.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 °,
Diffraction maximum is had at 16.90 ± 0.12 °.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 °,
Diffraction maximum is had at 17.40 ± 0.12 °.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 °,
16.90 ± 0.12 °, have diffraction maximum at 17.40 ± 0.12 °.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 °,
16.90 ± 0.12 °, have diffraction maximum, and salt free ligands at 17.25 ± 0.12 ° and 17.65 ± 0.12 ° at 17.40 ± 0.12 °
Peak.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 13.22 ± 0.12 °, 13.78
±0.12°、14.62±0.12°、16.12±0.12°、16.90±0.12°、17.40±0.12°、18.62±0.12°、
18.95 ± 0.12 °, 19.46 ± 0.12 °, 20.65 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 13.22 ± 0.12 °, 13.78
±0.12°、14.62±0.12°、16.12±0.12°、16.90±0.12°、17.40±0.12°、18.62±0.12°、
18.95 ± 0.12 °, 19.46 ± 0.12 °, 20.65 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °, and 17.25 ±
Salt free ligands peak at 0.12 ° and 17.65 ± 0.12 °.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22
±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、
17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±
0.12 °, 21.89 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22
±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、
17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±
0.12 °, 21.89 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °, and at 17.25 ± 0.12 ° and 17.65 ± 0.12 °
Salt free ligands peak.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22
±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、
17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±
0.12°、21.89±0.12°、22.68±0.12°、24.35±0.12°、25.38±0.12°、28.12±0.12°、28.49
± 0.12 °, have diffraction maximum at 29.37 ± 0.12 °.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22
±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、
17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±
0.12°、21.89±0.12°、22.68±0.12°、24.35±0.12°、25.38±0.12°、28.12±0.12°、28.49
± 0.12 °, have diffraction maximum, and salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 ° at 29.37 ± 0.12 °.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, has substantially as shown in Figure 1
Shown powder x-ray diffraction collection of illustrative plates.
The crystallization of any embodiment according to a fourth aspect of the present invention, it uses Cu-K α radiation, has substantially as shown in Figure 1
Shown powder x-ray diffraction collection of illustrative plates, and salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 °.
The crystallization of any embodiment according to either side of the present invention, this crystallization is transferred at the relative humidity conditions of 90%
Putting 5 hours, the amount absorbing water is less than 1%, preferably smaller than 0.75%, preferably smaller than 0.5%.
The crystallization of any embodiment according to either side of the present invention, when this crystallization reaches saturated in the water of 25 ± 1 DEG C,
The concentration of this saturated solution compounds of formula I is more than 4mg/ml more than 2mg/ml, such as concentration more than 3mg/ml, such as concentration,
Such as concentration is 2～10mg/ml more than 5mg/ml, such as its concentration, and such as its concentration is 3～10mg/ml, and such as its concentration is
4～10mg/ml, such as its concentration is 5～10mg/ml.
The crystallization of any embodiment according to either side of the present invention, during the size-reduced one-tenth of this crystallization fine powder, this is the thinnest
After powder disposes 5 minutes with the rotational speed of every point of kind 25 ± 1 turns in friability somascope, at the powder of friability somascope inwall
End residual volume (%) is less than 2%, e.g., less than 1.5%, e.g., less than 1%, e.g., less than 0.75%, e.g., less than 0.5%.
Further, fifth aspect present invention provides prepares the method for crystallization described in any one of either side of the present invention,
It includes making compound of formula I carry out the step processed in a solvent.Further, fifth aspect present invention provides and prepares this
The method of crystallization described in bright any one of either side, it comprises the steps:
(1) make to irrigate to be dissolved in first for western spit of fland free alkali (i.e. compound 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine)
In benzene, adding the hydrobromic acid (such as 47～the hydrobromic acid aqueous solution of 48%) of 0.95～1.05 equivalents, stirring and crystallizing, leaching precipitates
Thing, must irrigate for western spit of fland hydrobromate；
(2) make step (1) products therefrom 1 weight portion add in there-necked flask, add toluene 8～12 weight portion and water 0.8～
1.2 weight portions, after being heated to 85 DEG C of stirring and dissolving, cooling crystallization, the crystallization of leaching is dried at a temperature of 60-70 DEG C, obtains hydrogen bromine
Acid is fertile for Xi Ting；
(3) make step (2) products therefrom 1 weight portion add in there-necked flask, add acetone 10～15 weight portion, 55～60
DEG C stirring 20～40min makes pulp thing, is then stirred at room temperature 1～2 hour, filters, and gained crystallization vacuum drying obtains
The present invention crystallizes.
The method of any embodiment according to a fifth aspect of the present invention, wherein hydrobromic acid described in step (1) be 47～
The hydrobromic acid aqueous solution of 48%.
The method of any embodiment according to a fifth aspect of the present invention, wherein step (2) adds toluene 10 weight portion and
Water 1 weight portion.
The method of any embodiment according to a fifth aspect of the present invention, wherein adds acetone 12 weight portion in step (3).
The method of any embodiment according to a fifth aspect of the present invention, wherein adds acetone 12 weight portion in step (3),
55～60 DEG C of stirring 30min make pulp thing, are then stirred at room temperature 1.5 hours.
Surprisingly it has been found that make the hydrobromic acid obtained from toluene/water mixture irrigate for Xi Ting again through acetone treatment
After, to irrigate with the beta crystal hydrobromic acid of prior art report compared with replacing Xi Ting, this mode gained crystallizes in XRPD figure still 6.89
± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 ° etc. presents typical diffraction maximum, but 17.25
The typical diffractive peak presented without beta crystal at ± 0.12 ° and 17.65 ± 0.12 °, and 16.90 ± 0.12 °, 17.40 ±
New diffraction maximum occurs at 0.12 °.The crystallization of this novel crystal forms feature can be referred to as B crystal form hydrobromic acid in the present invention artificially and irrigate
For Xi Ting.It addition, it has also been unexpectedly found that, B crystal form hydrobromic acid of the present invention is fertile to be significantly higher than existing for Xi Ting not only solubility
Technology crystal formation, and hygroscopic capacity is little, and Electrostatic Absorption rate is low, and this is that prior art completely cannot be intended.
Yet further, sixth aspect present invention provides a kind of pharmaceutical composition, wherein comprises with compounds of Formula I,
And pharmaceutic adjuvant
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, wherein said compound of formula I is in this
The crystal form of any embodiment of bright either side.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, wherein said pharmaceutic adjuvant includes making
The carbohydrate used for diluent.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, wherein said carbohydrate is selected from: lactose, sweet
Dew alcohol, sorbierite, sucrose, particularly preferred carbohydrate is selected from: lactose, mannitol.The carbohydrate such as lactose, mannitol is to prepare solid system
The one excellent auxiliary material of class of agent particularly tablet, they as diluent individually or with other diluent such as starch, crystallite
When cellulose combination uses, the performance such as compressing tablet performance that tablet is excellent can be given under normal circumstances.Although lactose, mannitol
It is the conventional auxiliary material of tablet, but surprisingly it has been found that B crystal form hydrobromic acid of the present invention is fertile replaces Xi Ting and these carbohydrates when using
When pharmaceutical composition is prepared in combination, said composition presents low impurity during long-term storage and advances the speed.Unluckily
It is that the hydrobromic acid of other crystal form known is fertile by contrast is preparing pharmaceutical composition for Xi Ting with these carbohydrate combinations
Time, it is the most obvious that said composition impurity during long-term storage is advanced the speed.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, wherein comprises the described knot of 10 weight portions
Crystalline substance, and the described carbohydrate of 10～1000 weight portions.The described carbohydrate of such as 10～500 weight portions.Such as 10～300 weight portions
Described carbohydrate.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, it is oral solid formulation, such as tablet,
Capsule, granule.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the most also comprises selected from following auxiliary material:
(in addition to described carbohydrate) diluent, disintegrant, adhesive, lubricant.These auxiliary materials can according to conventional formulation such as
The conventional amount used of tablet selects.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, wherein said diluent is selected from: starch, micro-
Crystalline cellulose, calcium monohydrogen phosphate etc..In one embodiment, described diluent accounts for the 10～90% of composition total weight, such as
20～80%.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, wherein said disintegrant is selected from: glycolic
Sodium starch, PVPP, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose etc..A reality
Executing in scheme, described disintegrant accounts for the 2～10% of composition total weight, such as 2～7%.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, wherein said adhesive is selected from: hydroxypropyl
Methylcellulose, polyvinylpyrrolidone etc..In one embodiment, described adhesive account for composition total weight 2～
10%, such as 2～5%.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, wherein said lubricant is selected from: stearic acid,
Magnesium stearate, talcum powder, PEG4000～8000.In one embodiment, described lubricant account for composition total weight 1～
10%, such as 1～5%.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
With Cu-K α radiate, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, about 6.89 °, about 9.73 °, about 13.78 ° and
Diffraction maximum is had at about 14.62 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
With Cu-K α radiate, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, 6.89 ± 0.12 °, 9.73 ± 0.12 °,
Diffraction maximum is had at 13.78 ± 0.12 ° and 14.62 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
Radiate with Cu-K α, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, salt free ligands peak at 17.25 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
Radiate with Cu-K α, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, salt free ligands peak at 17.65 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
Radiate with Cu-K α, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, at 17.25 ± 0.12 ° and 17.65 ± 0.12 °
Salt free ligands peak, place.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
Radiate with Cu-K α, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, at 16.90 ± 0.12 °, have diffraction maximum.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
Radiate with Cu-K α, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, at 17.40 ± 0.12 °, have diffraction maximum.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
Radiate with Cu-K α, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, at 16.90 ± 0.12 ° and 17.40 ± 0.12 °
There is diffraction maximum at place.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
With Cu-K α radiate, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, 6.89 ± 0.12 °, 9.73 ± 0.12 °,
13.78 ± 0.12 °, 14.62 ± 0.12 °, have diffraction maximum at 16.90 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
With Cu-K α radiate, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, 6.89 ± 0.12 °, 9.73 ± 0.12 °,
13.78 ± 0.12 °, 14.62 ± 0.12 °, have diffraction maximum at 17.40 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
With Cu-K α radiate, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, 6.89 ± 0.12 °, 9.73 ± 0.12 °,
13.78 ± 0.12 °, 14.62 ± 0.12 °, 16.90 ± 0.12 °, have diffraction maximum at 17.40 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
With Cu-K α radiate, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, 6.89 ± 0.12 °, 9.73 ± 0.12 °,
13.78 ± 0.12 °, 14.62 ± 0.12 °, 16.90 ± 0.12 °, have diffraction maximum at 17.40 ± 0.12 °, and 17.25 ±
Salt free ligands peak at 0.12 ° and 17.65 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
With Cu-K α radiate, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, 6.89 ± 0.12 °, 8.42 ± 0.12 °,
9.73±0.12°、13.22±0.12°、13.78±0.12°、14.62±0.12°、16.12±0.12°、16.90±0.12°、
17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.65±0.12°、22.68±0.12°
There is diffraction maximum at place.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
With Cu-K α radiate, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, 6.89 ± 0.12 °, 8.42 ± 0.12 °,
9.73±0.12°、13.22±0.12°、13.78±0.12°、14.62±0.12°、16.12±0.12°、16.90±0.12°、
17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.65±0.12°、22.68±0.12°
There are diffraction maximum, and salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 ° in place.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
With Cu-K α radiate, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, 6.89 ± 0.12 °, 8.42 ± 0.12 °,
9.73±0.12°、11.90±0.12°、13.22±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、
16.12±0.12°、16.90±0.12°、17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±
0.12 °, 20.08 ± 0.12 °, 20.65 ± 0.12 °, 21.89 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
With Cu-K α radiate, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, 6.89 ± 0.12 °, 8.42 ± 0.12 °,
9.73±0.12°、11.90±0.12°、13.22±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、
16.12±0.12°、16.90±0.12°、17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±
0.12 °, 20.08 ± 0.12 °, 20.65 ± 0.12 °, 21.89 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °, and
Salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
With Cu-K α radiate, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, 6.89 ± 0.12 °, 8.42 ± 0.12 °,
9.73±0.12°、11.90±0.12°、13.22±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、
16.12±0.12°、16.90±0.12°、17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±
0.12°、20.08±0.12°、20.65±0.12°、21.89±0.12°、22.68±0.12°、24.35±0.12°、25.38
± 0.12 °, 28.12 ± 0.12 °, 28.49 ± 0.12 °, have diffraction maximum at 29.37 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
With Cu-K α radiate, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, 6.89 ± 0.12 °, 8.42 ± 0.12 °,
9.73±0.12°、11.90±0.12°、13.22±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、
16.12±0.12°、16.90±0.12°、17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±
0.12°、20.08±0.12°、20.65±0.12°、21.89±0.12°、22.68±0.12°、24.35±0.12°、25.38
± 0.12 °, 28.12 ± 0.12 °, 28.49 ± 0.12 °, have diffraction maximum at 29.37 ± 0.12 °, and at 17.25 ± 0.12 ° and
Salt free ligands peak at 17.65 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
Radiate with Cu-K α, there is powder x-ray diffraction collection of illustrative plates substantially as shown in.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I makes
Radiate with Cu-K α, there is powder x-ray diffraction collection of illustrative plates substantially as shown in, and at 17.25 ± 0.12 ° and 17.65
Salt free ligands peak at ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I exists
Placing 5 hours under the relative humidity conditions of 90%, the amount absorbing water is less than 1%, preferably smaller than 0.75%, preferably smaller than 0.5%.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization of wherein said compound of formula I exists
When reaching saturated in the water of 25 ± 1 DEG C, the concentration of this saturated solution compounds of formula I is more than 3mg/ more than 2mg/ml, such as concentration
It is 2～10mg/ml that ml, such as concentration are more than 5mg/ml, such as its concentration more than 4mg/ml, such as concentration, and such as its concentration is 3
～10mg/ml, such as its concentration are 4～10mg/ml, such as its concentration is 5～10mg/ml.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, the crystallization warp of wherein said compound of formula I
Be ground into fine powder time, this is after fine powder disposes 5 minutes with the rotational speed of every point of kind 25 ± 1 turns in friability somascope,
At the powder residual volume (%) of friability somascope inwall less than 2%, e.g., less than 1.5%, e.g., less than 1%, e.g., less than
0.75%, e.g., less than 0.5%.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, it uses Cu-K α radiation, with 2 θ angles
In the powder x-ray diffraction collection of illustrative plates represented, at about 6.89 °, about 9.73 °, about 13.78 ° and about 14.62 °, there is diffraction maximum.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, it uses Cu-K α radiation, with 2 θ angles
In the powder x-ray diffraction collection of illustrative plates represented, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 ° and 14.62 ±
Diffraction maximum is had at 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, it uses Cu-K α radiation, with 2 θ angles
In the powder x-ray diffraction collection of illustrative plates represented, salt free ligands peak at 17.25 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, it uses Cu-K α radiation, with 2 θ angles
In the powder x-ray diffraction collection of illustrative plates represented, salt free ligands peak at 17.65 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, it uses Cu-K α radiation, with 2 θ angles
In the powder x-ray diffraction collection of illustrative plates represented, salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, it uses Cu-K α radiation, with 2 θ angles
In the powder x-ray diffraction collection of illustrative plates represented, at 16.90 ± 0.12 °, there is diffraction maximum.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, it uses Cu-K α radiation, with 2 θ angles
In the powder x-ray diffraction collection of illustrative plates represented, at 17.40 ± 0.12 °, there is diffraction maximum.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, it uses Cu-K α radiation, with 2 θ angles
In the powder x-ray diffraction collection of illustrative plates represented, at 16.90 ± 0.12 ° and 17.40 ± 0.12 °, there is diffraction maximum.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, it uses Cu-K α radiation, with 2 θ angles
Represent powder x-ray diffraction collection of illustrative plates in, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ±
0.12 °, have diffraction maximum at 16.90 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, it uses Cu-K α radiation, with 2 θ angles
Represent powder x-ray diffraction collection of illustrative plates in, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ±
0.12 °, have diffraction maximum at 17.40 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, it uses Cu-K α radiation, with 2 θ angles
Represent powder x-ray diffraction collection of illustrative plates in, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ±
0.12 °, 16.90 ± 0.12 °, have diffraction maximum at 17.40 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, it uses Cu-K α radiation, with 2 θ angles
Represent powder x-ray diffraction collection of illustrative plates in, 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ±
0.12 °, 16.90 ± 0.12 °, have diffraction maximum at 17.40 ± 0.12 °, and at 17.25 ± 0.12 ° and 17.65 ± 0.12 °
Salt free ligands peak.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, it uses Cu-K α radiation, with 2 θ angles
Represent powder x-ray diffraction collection of illustrative plates in, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 13.22 ±
0.12°、13.78±0.12°、14.62±0.12°、16.12±0.12°、16.90±0.12°、17.40±0.12°、18.62
± 0.12 °, 18.95 ± 0.12 °, 19.46 ± 0.12 °, 20.65 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, it uses Cu-K α radiation, with 2 θ angles
Represent powder x-ray diffraction collection of illustrative plates in, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 13.22 ±
0.12°、13.78±0.12°、14.62±0.12°、16.12±0.12°、16.90±0.12°、17.40±0.12°、18.62
± 0.12 °, 18.95 ± 0.12 °, 19.46 ± 0.12 °, 20.65 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °, and
Salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, it uses Cu-K α radiation, with 2 θ angles
Represent powder x-ray diffraction collection of illustrative plates in, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ±
0.12°、13.22±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90
±0.12°、17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、
20.65 ± 0.12 °, 21.89 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, it uses Cu-K α radiation, with 2 θ angles
Represent powder x-ray diffraction collection of illustrative plates in, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ±
0.12°、13.22±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90
±0.12°、17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、
20.65 ± 0.12 °, 21.89 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °, and 17.25 ± 0.12 ° and 17.65 ±
Salt free ligands peak at 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, it uses Cu-K α radiation, with 2 θ angles
Represent powder x-ray diffraction collection of illustrative plates in, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ±
0.12°、13.22±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90
±0.12°、17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、
20.65±0.12°、21.89±0.12°、22.68±0.12°、24.35±0.12°、25.38±0.12°、28.12±
0.12 °, 28.49 ± 0.12 °, have diffraction maximum at 29.37 ± 0.12 °.
The pharmaceutical composition of any embodiment according to a sixth aspect of the present invention, it uses Cu-K α radiation, with 2 θ angles
Represent powder x-ray diffraction collection of illustrative plates in, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ±
0.12°、13.22±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90
±0.12°、17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、
20.65±0.12°、21.89±0.12°、22.68±0.12°、24.35±0.12°、25.38±0.12°、28.12±
0.12 °, 28.49 ± 0.12 °, have diffraction maximum at 29.37 ± 0.12 °, and at 17.25 ± 0.12 ° and 17.65 ± 0.12 °
Salt free ligands peak.
In further aspect of the present invention, it is provided that carbohydrate (it is lactose and/or mannitol) comprises the present invention in preparation
Purposes in the medicine of the compound of formula I crystallization of either side any embodiment, wherein said carbohydrate makes impurity gather way
Suppressed.In one embodiment, described carbohydrate makes impurity gather way to be able to suppression and refer to, contained described crystallization and sugar
Total impurities increments when the medicine of class is placed 5 months in 40 DEG C of insulating boxs is less than 100%, e.g., less than 75%, the least
In 50%.In one embodiment, described medicine comprises the described crystallization of 10 weight portions, and 10～1000 weight portions
Described carbohydrate, the described carbohydrate of such as 10～500 weight portions, the described carbohydrate of such as 10～300 weight portions.
In further aspect of the present invention, it is provided that compound of formula I described in either side any embodiment of the present invention
Crystallize in the purposes prepared in the medicine of the disease preventing or treating central nervous system to be correlated with.An embodiment
In, the disease that described central nervous system is relevant is selected from: the disturbance of emotion, depression, major depressive disorder, post-natal depression and
Relevant depression, Alzheimer's disease, mental disease, cancer, old-age group or the Parkinson's disease of Bipolar Disorder, anxiety, extensively
Property anxiety disorder, social anxiety disorder, obsession, panic disorder, panic attack, neurosis, social phobia, agoraphobe, pressure
The power urinary incontinence, vomiting, IBS, eating disorder, chronic ache, part response, treatment repellence depression, Alzheimer's disease,
Cognitive impairment, ADHD, melancholia, PTSD, upsurge, sleep apnea, excessive drinking, nicotine or carbohydrate habituation,
Drug abuse and alcohol or drug abuse, pain.In one embodiment, described pain is selected from: phantom limb pain, nerve are ached
Bitterly, diabetic neuropathy, post-herpetic neuralgia (PHN), complication of wrist (CTS), HIV DPN, complexity
Regional Pain Syndrome (CPRS), trigeminal neuralgia/trigeminal neuralgia pain/trismus dolorificus, operation (the most postoperative town
The opposing of capillary that bitterly), diabetic vascular complications is relevant with insulin or the diabetic symptom pain relevant with angina pectoris,
Pain and the pain of related to cancer relevant with menstruation, have a toothache, have a headache, antimigraine, tension headache, trigeminal neuralgia, temporo jaw
Syndromes, myofacial pain muscle damage syndrome, FMS, bone joint pain (osteoarthritis), rheumatism
Property arthritis and rheumatic arthritis and burn relevant rheumatic arthritis and the oedema caused with the relevant wound of burn,
Cause due to osteoarthritis sprains or the reason of fracture pain, osteoporosis, Bone tumour or the unknown, gout, fiber group
Knit inflammation, myofacial pain, syndrome of chest outlet, upper back pain or back pain (wherein back pain by systematicness, local or
Primary spine disease (radiculopathy)), Pelvic pain, heart source property pectoralgia, NCCP and spinal cord injury (SCI)
Relevant pain, Post stroke pain, Cancer neuropathy, AIDS pain, sickle cell's pain or old pain.
Arbitrary technical characteristic that any embodiment of either side of the present invention or this either side is had is equally applicable
Other any embodiment or any embodiment of other either side, as long as they will not be conflicting, certainly mutually
Between where applicable, if necessary can make individual features suitably to modify.Make into one with feature the most to various aspects of the present invention
The description of step.
All documents recited in the present invention, their full content is incorporated herein by, and if these literary compositions
Offer expressed implication and the present invention inconsistent time, be as the criterion with the statement of the present invention.Additionally, the present invention use various terms and
Phrase has and well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this these terms and
Phrase is described in more detail and explains, the term mentioned and phrase are if any inconsistent with common art-recognized meanings, with institute of the present invention table
The implication stated is as the criterion.
It is further described the most to various aspects of the present invention.
Cortex and the transmission of hippocampus cholinergic nerve are very important for cognition, and substantial amounts of preliminary clinical observations refers to
Go out the biotin acceptor IA (5-HT1A) importance for described system.T.Koyama at Neurosci.Lett., 265,33-
Reporting in 36,1999,5-HT1A activator BAYX3702 increases in rat acetylcholine by the outflow in cortex and hippocampus.
It is interesting that 5-HT1A antagonist WAY-100635 can eliminate the impact of BAYX3702, show that the impact of BAYX3702 is 5-
HT1A mediation.
Substantial amounts of research is it has been reported that the effect to cognitive impairment of the 5-HT1A conditioning agent.A.Meneses exists
Neurobiol.Learn.Memory, 71,207-218, report in 1999, part 5-HT1A activator (±)-8-hydroxyl-2-
(diη-propyl amino)-1,2,3,4-tetrahydro-naphthalene, HCl (8-OH-DPAT) promotes the study of normal rat and consolidates, and makes
The cognitive function normalization of cognitive impairment rat.
These preclinical observed results seem to have reflected in clinic.T Sumiyoshi at Am.J.Psych.,
158,1722-1725,2001 report such research, wherein make patient accept typical antipsychotics (such as fluorine piperazine
Butylbenzene, Sulpiride and guanidine fan are clear, and these the most do not have 5-HT1A activity) and placebo or Tandospirone (it is sharp for 5-HT1A
Dynamic agent).On the basis of antipsychotics, accept the patient of Tandospirone show as their cognitive ability and improved, and
The patient accepting placebo does not the most obtain this improvement.It is similar to, atypical antipsychotics (such as Clozapine, its
Also for 5-HT1A activator) enhance the cognitive ability of schizophreniac, and typical antipsychotics (such as fluorine piperazine
Butylbenzene, it does not have 5-HT1A activity) the most not there is this enhancing effect, see Y.Chung, Brain Res., 1023,54-
63,2004.
As it has been described above, cholinergic system is considered relevant with the neuron event of regulation cognition, and cholinergic system can
By serotonin receptor 3 (5-HT3) suppressed control [(Giovannini etc., J Pharmacol Exp Ther 1998,285:
1219-1225；Costall and Naylor, Current Drug Targets-CNS&Neurobiol Disord 2004,3:
27-37)]。
In the adaptive testing of mouse, in operation alternately is forced in the T labyrinth of rat, and the target resolution marmoset
And in the operation of reversal learning, Ondansetron reduces by muscarine, hyoscine or the cholinergic way occurred in basal nuclei
The damage in footpath and damage (Barnes etc., the Pharamcol Biochem Behav 1990,35:955-962 that causes；Carey
Deng, PharamcolBiochem Behav 1992,42:75-83).Boast et al. (Neurobiol Learn Mem1999,
71:259-271) MK-801 (noncompetitive antaganist of a kind of nmda receptor) is used to destroy at that postpone and sample eight arm
The cognitive ability of the rat of training in the system that labyrinth operation is non-matching.Ondansetron demonstrates and has blocked cognitive impairment.Additionally,
In the research of the amnesia in the passive avoidance of Mice Hepatocytes Injured by Ethanol, this amnesia of ethanol can be by Ondansetron portion
Ground is divided to recover to normal (Napiorkowska-Pawlak etc., Fundam Clin pharmacol 2000,14:125-131).
Therefore, in preclinical model, after cholinergic system is damaged, the antagonism of 5-HT3 can promote cholinergic
Transmission (Diez-Ariza etc., Psychopharmacology2003,169:35-41；Gil-Bea etc., Neuropharmcol
2004,47:225-232) the above-mentioned methods for the treatment of of employing, is indicated to treat the basis of cognitive disorders.
In the randomized double-blind crossing research of healthy male study subject, the assessment situation of language and spatial memory and holding
Continuous constant memory proves, 5-HT3 antagonist (Alosetron) reduces the language of hyoscine induction and spatial memory
Defect (Preston, Recent Advances in thetreatment of Neurodegenerative
Disordersand cognitive function, 1994, (editor) Racagni and Langer, Basel Karger, 89-93
Page).
In a word, it is believed that the compound playing 5-HT1A partial agonist activity and 5-HT3 antagonist activities is the most available
In treatment cognitive impairment.Additionally play serotonin reabsorption inhibitory action compound be particularly useful for treat relevant with depression
Cognitive impairment, this is because the partial agonist effect that the inhibitory action of serotonin reabsorption combines 5-HT1A will make to press down in treatment
Can be with quick acting during strongly fragrant disease.
It is known that the compound of the present invention is effective inhibitor of human serum element transporter, i.e. they inhibit thrombocytin
Re-absorption.Additionally, described compound is mouse, rat, cavy and effective antagonist of dog 5-HT3 acceptor.It is subject at people 5-HT3
In body (it is cloned in egg mother cell), the compound described in discovery is antagonist when low concentration (IC50 is about 30nM),
And when higher concentration (ED50=2.1 μM), described compound shows agonist characteristics.The compound of the present invention is with high concentration
Application subsequently do not demonstrate any exciting response, this be likely due in vitro Rapid desensitization or directly antagonism caused.
Therefore, the compound of the present invention of low concentration demonstrates significant antagonism to people's 5-HT3 acceptor, and this is at other species
5-HT3 acceptor in can also be observed that.
In the brain homogenate of rat and mouse, the compound of the present invention is combined with 5-HT1A acceptor with extremely low compatibility.
But, the compound of the present invention is combined with people's 5-HT1A acceptor with the Ki of 40nM.Additionally, performance data shows, the change of the present invention
The partial agonist of compound behaviour 5-HT1A acceptor, is shown as the effect of 85%.
It is expected that the activity to SERT, 5-HT3-and 5-HT1A acceptor contributes to described compound in human body in the present invention
Performance.
It is known that the compound of the present invention makes the outer water of born of the same parents of the acetylcholine in the prefrontal cortex of rat and ventral hippocampus
Flat increase.These preclinical discoveries wish to be converted into the clinical effectiveness for the treatment of cognitive impairment, so, at such as alzheimer '
In mos disease, the treatment to cognitive impairment employs the inhibitor of acetylcholinesterase.Propping up further above-mentioned position
Holding and can find in embodiment 27, wherein the data obtained shows, the compound of the present invention enhances the background memory of rat.Always
It, the pharmacology performance of the compounds of this invention combines with to the effect of levels of acetylcholine, and the memory of rat is consumingly
Showing, the compound of the present invention can be used for treating cognitive impairment.
In one embodiment, the present invention relates to treat cognitive defect or the method for cognitive impairment, the method include to
Need this compound of patient's drug treatment effective dose of the compounds of this invention.
Cognitive defect or cognitive impairment include cognitive function or cognitive domain (such as working memory, notice and alertness,
Language learning and memory, visual learning and memory, reasoning and the solution to problem, as performed function, processing speed and/or society
Cognitive) decline.Specifically, cognitive defect and cognitive impairment can show as lacking notice, thinking is disintegrated, thinking is delayed
Slowly, understand difficulty, notice concentrate difficulty, problem-solving ability to damage, poor memory, thought expression difficult and/or
It is difficult to make thought, emotion and behavior integration or be difficult to eliminate unrelated thought.Term " cognitive defect " and " cognitive impairment " are
Refer to the identical meaning, and be used interchangeably.
In one embodiment, described patient is also diagnosed has other CNS disorder, such as Affective Disorder, as
Depressed；Broad sense is depressed；Major depressive disorder；Anxiety disorder, including GAD and panic disorder；Obsession；Spirit point
Split disease；Parkinson's disease；Dull-witted；AIDS is dull-witted；ADHD；The memory impairment that age is relevant；Or Alzheimer's disease.
Cognitive impairment is one of characteristic feature of depression (such as major depressive disorder).From the improvement of depressive state also
For making in the improved meaning of cognitive impairment, cognitive disorders to a certain extent may be inferior to depression.But, also have clear
The evidence of Chu shows, cognitive disorders is in fact unrelated with depression.Such as, there is research display, recovered from depression
Time, cognitive impairment still can continue [J.Nervous Mental Disease, 185,748-754,197].Additionally, antidepressant pair
Depressed and cognitive impairment different-effect provides support for following viewpoint further, and described viewpoint is: although depressed with recognize
Know that damage often and deposits generation, but depressed unrelated with cognitive impairment.Although thrombocytin and norepinephrine medicine make depression
Symptom is considerably improved, but many studies have shown that, regulation norepinephrine system will not be such as regulation blood
Improve as clear element cognitive function [Brain Res.Bull, 58,345-350,2002；Hum Psychpharmacol, 8,
41-47,1993].
It is believed that the cognitive impairment treating depressive patient by being administered the compound of the present invention is particularly advantageous.It is expected that
The polynary pharmacology (multifaceted pharmacology) of the compounds of this invention (specifically to SERT, 5-HT3 and
The activity of 5-HT1A) cognitive function is improved and makes the treatment of depressive state is able to quick acting.
In the elderly, cognitive impairment is the consideration of particular importance.Cognitive impairment generally becomes along with the increase at age
Seriously, and become serious further along with the generation of depression.Therefore, in one embodiment, cognitive impairment to be treated
Patient be the elderly, particularly suffer from the elderly of depression.
As described above, in schizophreniac, cognitive function generally sustains damage.Additionally, many researchs are
Conclude, in schizophrenia, cognitive function relevant with occupational function [Scizophrenia Res., 45,175-184,
2000].In one embodiment, the patient of cognitive impairment to be treated is schizophreniac.
5-HT3 receptor antagonist is proposed for the most again treating such as vomiting, the vomiting of chemotherapy induction, habituation, medicine
Abuse, pain, IBS (IBS), schizophrenia and eating disorder [Eur.J.Pharmacol, 560,1-8,
2007；Pharmacol.Therapeut., 111,855-876,2006；Alimentary Pharmacol.Ther., 24,183-
205,2006].
Clinical research shows, the depressive patient treating clinical response insufficient that Mirtazapine and SSRI combined is better than
(treatment refractory depression, TRD or repellence are depressed to treat the insufficient depressive patient of clinical response to be used alone SSRI
Disease) [Psychother.Psychosom., 75,139-153,2006].Mirtazapine is the antagonist of 5-HT2 and 5-HT3, and it is
Following viewpoint provides support, and described viewpoint is: the compound of the present invention can be used for treating TRD.
Upsurge is the symptom relevant with menopause transition.Some women can suffer from the interference of generally up to attending the meeting of this symptom and sleep
Sleep or the degree of behavior, and reach to need the degree for the treatment of.In decades, the HRT, hormone replacement therapy of use estrogen is had built up
Put into practice, but recently, its side effect (such as breast cancer and cardiac event) is proposed concern.SSRI is used to carry out
Clinical testing shows, these compounds have an effect to upsurge, but effect less than estrogen [J.Am.Med.Ass., 295,
2057-2071,2006].But, use the compound (compound of the such as present invention) of suppression serotonin reabsorption to treat heat
Tide is probably the alternative methods for the treatment of of the women that can not or be reluctant to accept estrogen.
Sleep-respiratory, obstruction sleep apnea-hypopnea syndrome or obstructive sleep respiratory disorder are a kind of disorderly
Disorderly, its effective medicinal treatment still has to be determined.But, many zooscopies show, 5-HT3 antagonist be (the such as present invention's
Compound) can effectively treat these diseases [Sleep, 21,131-136,1998；Sleep, 8,871,878,2001].
In one embodiment, the method that the present invention relates to treat disease, the method includes to needs chemical combination of the present invention
This compound of patient's drug treatment effective dose of thing, wherein said disease is selected from: the disturbance of emotion, depression, Major Depressive
Depression, Alzheimer's disease, mental disease, cancer, old-age group or handkerchief disorderly, that post-natal depression is relevant with Bipolar Disorder
Gold Sen Shi disease, anxiety, GAD, social anxiety disorder, obsession, panic disorder, panic attack, neurosis, social activity are probably
Fear disease, agoraphobe, stress incontinence, vomiting, IBS, eating disorder, chronic ache, part response, treatment repellence press down
Strongly fragrant, Alzheimer's disease, cognitive impairment, ADHD, melancholia, PTSD, upsurge, sleep apnea, excessive drinking, nicotine
Or carbohydrate habituation, drug abuse and alcohol or drug abuse.In one embodiment, above-mentioned listed disease to be treated
In the patient of any one disease be initially diagnosed as suffering from described disease.
In one embodiment, the crystallization that the present invention relates to formula I is being prepared for treating disease
Purposes in medicine, wherein said disease is selected from: the disturbance of emotion, depression, major depressive disorder, post-natal depression are with double
Relevant depression, Alzheimer's disease, mental disease, cancer, old-age group or the Parkinson's disease of phase phrenoblabia, anxiety, popularity
Anxiety disorder, social anxiety disorder, obsession, panic disorder, panic attack, neurosis, social phobia, agoraphobe, pressure
Property the urinary incontinence, vomiting, IBS, eating disorder, chronic ache, part response, treatment repellence depression, Alzheimer's disease, recognize
Know damage, ADHD, melancholia, PTSD, upsurge, sleep apnea, excessive drinking, nicotine or carbohydrate habituation, medicine
Thing abuse and alcohol or drug abuse.In one embodiment, any one disease in above-mentioned listed disease to be treated
Patient is initially diagnosed as suffering from described disease.
It is well known that, use general CI and use special SSRI to carry out treatment may be with sex dysfunction
Relevant, and this normally results in treatment and interrupts.The patient's report property of the there occurs functional defect relating to SSRI of up to 30-70%
[J.Clin.Psych., 66,844-848,2005], this defect includes: sexual desire reduces, and orgasm postpones, reduces or lack,
Sexual stimulus goes down and erectile dysfunction.In clinical testing, have 114 study subjects and received the change of the present invention
Compound: in these 114 study subjects, only 1 study subject report there occurs sex dysfunction.These data show, make
The another people of clinical intervention is carried out relevant with property functional defect the most hardly with the compound of the present invention.
It is known that the compound of the present invention is particularly well applicable for treating chronic ache.Chronic ache include following these
Sign, such as phantom limb pain, neuropathic pain, diabetic neuropathy, post-herpetic neuralgia (PHN), complication of wrist
(CTS), HIV DPN, Complex regional pain syndrome (CPRS), trigeminal neuralgia/trigeminal neuralgia pain/property bitterly are taken out
Jerk, the opposing of capillary that operation (such as Postoperative Analgesia After), diabetic vascular complications are relevant with insulin or diabetes
The shape pain relevant with angina pectoris pain and the pain of related to cancer relevant with menstruation, have a toothache, have a headache, antimigraine, anxiety
Property headache, trigeminal neuralgia, temporomandibular joint syndrome, myofacial pain muscle damage syndrome, FMS, bone close
Joint pain (osteoarthritis), rheumatic arthritis and rheumatic arthritis and burn relevant rheumatic arthritis and with burn
Oedema that relevant wound causes, spraining or fracture pain, osteoporosis, Bone tumour or not of causing due to osteoarthritis
Reason, gout, fibrositis, myofacial pain, syndrome of chest outlet, upper back pain or the back pain known (are wherein carried on the back
Portion's pain by systematicness, local or primary spine disease (radiculopathy)), Pelvic pain, heart source property pectoralgia, non-heart source property
Pain that pectoralgia is relevant to spinal cord injury (SCI), Post stroke pain, Cancer neuropathy, AIDS pain, sickle cell's pain
Or pain in old age.Therefore, in one embodiment, above-mentioned chronic pain is being prepared in the crystallization that the present invention relates to the compounds of this invention
Purposes in the medicine of pain.
" therapeutically effective amount " of compound used herein refers to during Results, it is sufficient to cures, subtract
Light or part suppresses the amount of the clinical manifestation of given disease and complication thereof, and wherein said Results includes being administered described
Compound.The amount sufficiently achieving above-mentioned purpose is defined as " therapeutically effective amount ".Effective dose for numerous purposes depends on disease
Sick or the order of severity of damage and the body weight of study subject and overall status.It should be understood that use conventional test method, logical
Crossing the matrix of structure value and points different in this matrix is carried out test may determine that suitable dosage, these technology are all being passed through
Within the scope of the such those of ordinary skill of doctor of training is grasped.
Term used herein " is treated " and " process " refers to be managed patient and nurse reaching to resist such as
The purpose of the symptom of disease or disorder etc.Above-mentioned term includes the given symptom that suffered from for patient and controlling of taking in advance
The four corner treated, such as, be administered described reactive compound to alleviate described symptom or complication, postpone disease, disorder or
The process of symptom, alleviate or alleviate described in symptom or complication, and/or cure or eliminate a disease, disorderly or symptom and pre-
Anti-described symptom, wherein prevention is interpreted as being managed patient and nurse reaching to resist disease, symptom or disorder
Purpose, it includes being administered described reactive compound with the symptom described in prevention or the outbreak of complication.But, preventative (pre-
Prevent) and therapeutic (curative) treatment be two independent aspects of the present invention.Patient to be treated is preferably mammal,
Particularly people.
Generally, the methods for the treatment of of the present invention relates to the compound being given daily the present invention.This can include once a day to
Medicine, twice administration every day, it is administered the most frequently.
In one embodiment, the compound that the present invention relates to the present invention is manufacturing for the medicine treating following disease
In purposes, described disease is: the disturbance of emotion, depression, major depressive disorder, post-natal depression have with Bipolar Disorder
Depression, Alzheimer's disease, mental disease, cancer, old-age group or the Parkinson's disease of pass, anxiety, GAD, social Jiao
Consider disease, obsession, panic disorder, panic attack, neurosis, social phobia, agoraphobe, stress incontinence, vomiting,
IBS, eating disorder, chronic ache, part response, treatment repellence depression, Alzheimer's disease, cognitive impairment, ADHD, essence
God's melancholia, PTSD, upsurge, sleep apnea, excessive drinking, nicotine or carbohydrate habituation, drug abuse and alcohol or
Drug abuse.
In one embodiment, the present invention relates to the compound of the present invention for treating following disease, described disease
For: the disturbance of emotion, depression, major depressive disorder, the post-natal depression depression relevant with Bipolar Disorder, alzheimer '
Mos disease, mental disease, cancer, old-age group or Parkinson's disease, anxiety, GAD, social anxiety disorder, obsession, terrified
Obstacle, panic attack, neurosis, social phobia, agoraphobe, stress incontinence, vomiting, IBS, eating disorder, slow
Property pain, part response, treatment repellence depression, Alzheimer's disease, cognitive impairment, ADHD, melancholia, PTSD,
Upsurge, sleep apnea, excessive drinking, nicotine or carbohydrate habituation, drug abuse and alcohol or drug abuse.
The compound cognitive effect to people of the present invention can be evaluated in many ways.Can be in multiple tests
Effect described in evaluation, is wherein administered the compound of the present invention, then at recognition tests (such as auditory verbal to healthy volunteer
Learning test (AVLT), Weis-senberg number (WCST) or the test of notice continuation) middle mensuration this health aspiration
The cognitive ability of person [Psycopharmacol, 163,106-110,2002；Psychiatry Clin.Neurosci., 60,70-
76,2006].It is, of course, also possible to use identical method of testing to evaluate described effect in the patient suffer from cognitive impairment.Can
Other modes for selecting are can to use cognitive model, wherein induce the cognitive impairment of healthy volunteer, and to this
The recovery effect of bright compound is measured.Cognitive impairment can pass through such as hyoscine, sleep deprivation, alcohol and tryptophan
Consume and induce.
The pharmaceutical formulation of the present invention can be prepared by method conventional in the art.It is especially mentioned that tablet,
Tablet can be by mixing active component with common adjuvant and/or diluent, subsequently by the mixture of gained in routine
Prepared by pelleter.The example of adjuvant or diluent includes: calcium phosphate dibasic anhydrous, PVP, PVP-VA copolymer, crystallite
Cellulose, sodium starch glycollate, starch, mannitol, farina, talcum, magnesium stearate, gelatin, lactose, natural gum etc..
Can use in order to achieve the above object and any other adjuvant normally used or additive are (such as colouring agent, flavor enhancement, anti-
Rotten agent etc.), precursor conditions be these adjuvants or additive compatible with described active component.
The solution for injection is prepared: be dissolved in active component and feasible additive for noting by procedure below
In the partial solvent (preferably sterilized water) penetrated, gained solution is adjusted to required volume, by this solution sterilization, and by this solution
Fill to suitable ampoule or bottle.Any suitable additive usually used in this field, such as Zhang Du can be added
Agent, preservative, antioxidant etc..
The pharmaceutical composition of the present invention or those materials constructed in accordance can be given by any suitable approach
Medicine, described approach for example: the forms such as tablet, capsule, powder, syrup can be taken orally, or injection solution form is permissible
Parenteral.In order to prepare described composition, method well known in the art can be used, and can use in this area
Normally used any pharmaceutically useful carrier, diluent, excipient or other additives.
Easily, the compound of the present invention is administered in a unit, and described UD comprises with Formulas I chemical combination
The described compound of the free base of thing about 1 to 50mg.It is believed that the concentration dependant situation according to 5-HT3 activity sets use
The upper limit.Total dose of every day is typically about 1-20mg, e.g., from about 1 to 10mg, about 5-10mg, about 10-20mg or about 10-15mg's
The compound of the present invention.It is especially mentioned that dose every day is 5,10,15 or 20mg with the free base of compound of formula I.
The tablet comprising the compounds of this invention can be prepared easily by the particle of wetting.Use the method, by dry state
Solid (active component, filler, binding agent etc.) be blended, and get wet with water or other wetting agent (such as alcohol), then make
Become aggregate or the particle of moist solids.Persistently carry out soaking pill block to process, until obtaining required uniform particle diameter, so
After granular product is dried.The compound of the present invention is generally and lactose, starch and copolyvidone (copovidone) are at height
Shear mixer is mixed together with water.After forming particle, these particles are sieved in the screen cloth have appropriate mesh, and does
Dry.Then, the particle being dried of gained is mixed with microcrystalline cellulose, croscarmellose sodium and magnesium stearate, then presses
Sheet.Other alternative modes are, it is possible to use mannitol, starch and copolyvidone prepare the wet method of the compounds of this invention
Granulation, then mixes this particle with microcrystalline cellulose, sodium starch glycollate and magnesium stearate, carries out compressing tablet afterwards.It is available for
Other modes selected are, by using calcium phosphate dibasic anhydrous, starch and copolyvidone to prepare the wet method of the compounds of this invention
Granulation, then mixes this particle with microcrystalline cellulose, sodium starch glycollate (A type), talcum and magnesium stearate, carries out afterwards
Compressing tablet.Copolyvidone is PVP-VA copolymer.
In one embodiment, the crystallization (it can be described as B crystal form in the present invention) of the compound of formula I of the present invention, and
And suitably tablet can be constituted (percentage composition shown in it is w/w%) as follows:
B crystal form 2-20%, lactose 30-50%, starch 15-30%, copolyvidone 3-5%, microcrystalline cellulose 15-25%,
Croscarmellose sodium 2-5%, magnesium stearate 0.5-5%.
Particularly, described tablet can be constituted as follows:
B crystal form 3-4%, lactose 44-46%, starch 22-23%, copolyvidone 3-4%, microcrystalline cellulose 20-22%, friendship
Connection hydroxyl methylcellulose sodium 3-3.5%, magnesium stearate 0.5-1%；
Or, B crystal form 15-16%, lactose 35-38%, starch 18-20%, copolyvidone 3-4%, microcrystalline cellulose 20-
22%, croscarmellose sodium 3-3.5%, magnesium stearate 0.5-1%；
Or, B crystal form 1-2%, lactose 44-46%, starch 20-24%, copolyvidone 3-4%, microcrystalline cellulose 22-
24%, croscarmellose sodium 3-4%, magnesium stearate 0.5-1%.
In one embodiment, the crystallization (it can be described as B crystal form in the present invention) of the compound of formula I of the present invention, and
And suitably tablet may be constructed as follows:
B crystal form 2-30%, mannitol 25-45%, starch 10-20%, copolyvidone 2-4%, microcrystalline cellulose 22-
27%, sodium starch glycollate 4-5%, magnesium stearate 0.25-5% (such as 0.25-2%)
Particularly, described tablet can be constituted as follows:
B crystal form 20-22%, mannitol 35-36%, starch 10-12%, copolyvidone 2.5-3%, microcrystalline cellulose 24-
25%, sodium starch glycollate 3-4%, magnesium stearate 0.25-1%；
Or, B crystal form 12-13%, mannitol 36-37%, starch 18-19%, copolyvidone 3-4%, microcrystalline cellulose
24-25%, sodium starch glycollate 3-4%, magnesium stearate 0.25-1%；
Or, B crystal form 25-27%, mannitol 27-29%, starch 13-15%, copolyvidone 3-4%, microcrystalline cellulose
24-25%, sodium starch glycollate 3-5%, magnesium stearate 0.25-1%；
Or, B crystal form 3-4%, mannitol 40-42%, starch 20-22%, copolyvidone 3-4%, microcrystalline cellulose 26-
28%, sodium starch glycollate 3-5%, magnesium stearate 0.5%.
Different amounts of by selecting the tablet of the correct amount of the compounds of this invention and suitable dimension to obtain to have
The tablet of reactive compound (such as corresponding to 2.5,5,10,20,25,30,40,50,60 or the free alkali of 80mg).
Accompanying drawing explanation
The x-ray diffractogram of powder of compound of formula I crystallization prepared by Fig. 1: the present invention.
Detailed description of the invention
The present invention can be conducted further description by the following examples, but, the scope of the present invention does not limit
In following embodiment.One of skill in the art is it is understood that on the premise of without departing substantially from the spirit and scope of the present invention, permissible
The present invention is carried out various change and modification.The present invention to test used in material and test method carry out generality
And/or concrete description.Although being to it is known in the art that by realizing many materials that the object of the invention used and method of operating
But the present invention still describes in detail as far as possible at this.
The present invention can be conducted further description by the following examples, but, the scope of the present invention does not limit
In following embodiment.One of skill in the art is it is understood that on the premise of without departing substantially from the spirit and scope of the present invention, permissible
The present invention is carried out various change and modification.The present invention to test used in material and test method carry out generality
And/or concrete description.Although being to it is known in the art that by realizing many materials that the object of the invention used and method of operating
But the present invention still describes in detail as far as possible at this.Following example further illustrate the present invention rather than limit this
Bright.
When the following crystallization preparing formula I, the fertile of use can be directly with reference to existing for western spit of fland free alkali
There is technical method to prepare, such as the method described in CN1561336A, CN101472906A etc., and use second when necessary
Acetoacetic ester purifies the HPLC purity making active component more than 98%, in order to for ensuing one-tenth salt and crystallization.
Powder x-ray diffraction analysis of the present invention (XRPD the most generally said analyzes), uses CN101472906B specification
[0229] section institute's support method and condition are carried out, and this method of testing generally also known as uses Cu-K α radiation in this area, can obtain
To the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles.
Measurement result: the powder x-ray diffraction figure such as accompanying drawing 1 of Examples below 1 gained compound of formula I of the present invention, wherein
Display, this compound is crystalline solid, its x-ray diffractogram of powder have 2 θ angles be 6.89 ± 0.12 °, 9.73 ± 0.12 °,
13.78 ± 0.12 ° and the diffraction maximum of 14.62 ± 0.12 °.
Especially, this diffraction pattern salt free ligands peak at 17.25 ± 0.12 °.Especially, this diffraction pattern is at 17.65 ± 0.12 °
Salt free ligands peak, place.Especially, this diffraction pattern salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 °.Especially, this spreads out
Penetrate figure and have diffraction maximum at 16.90 ± 0.12 °.Especially, this diffraction pattern has diffraction maximum at 17.40 ± 0.12 °.Especially,
This diffraction pattern has diffraction maximum at 16.90 ± 0.12 ° and 17.40 ± 0.12 °.Especially, this diffraction pattern 6.89 ± 0.12 °,
9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 °, have diffraction maximum at 16.90 ± 0.12 °.Especially, this diffraction pattern
6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 °, have diffraction maximum at 17.40 ± 0.12 °.Special
Not, this diffraction pattern 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 °, 14.62 ± 0.12 °, 16.90 ±
0.12 °, have diffraction maximum at 17.40 ± 0.12 °.Especially, this diffraction pattern 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ±
0.12 °, 14.62 ± 0.12 °, 16.90 ± 0.12 °, have diffraction maximum at 17.40 ± 0.12 °, and at 17.25 ± 0.12 ° and
Salt free ligands peak at 17.65 ± 0.12 °.Especially, this diffraction pattern 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °,
13.22±0.12°、13.78±0.12°、14.62±0.12°、16.12±0.12°、16.90±0.12°、17.40±
0.12 °, 18.62 ± 0.12 °, 18.95 ± 0.12 °, 19.46 ± 0.12 °, 20.65 ± 0.12 °, have at 22.68 ± 0.12 ° and spread out
Penetrate peak.Especially, this diffraction pattern 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 13.22 ± 0.12 °, 13.78
±0.12°、14.62±0.12°、16.12±0.12°、16.90±0.12°、17.40±0.12°、18.62±0.12°、
18.95 ± 0.12 °, 19.46 ± 0.12 °, 20.65 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °, and 17.25 ±
Salt free ligands peak at 0.12 ° and 17.65 ± 0.12 °.Especially, this diffraction pattern 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ±
0.12°、11.90±0.12°、13.22±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12
±0.12°、16.90±0.12°、17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、
20.08 ± 0.12 °, 20.65 ± 0.12 °, 21.89 ± 0.12 °, have diffraction maximum at 22.68 ± 0.12 °.Especially, this diffraction pattern
6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22 ± 0.12 °, 13.78 ± 0.12 °,
14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、17.40±0.12°、18.62±
0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±0.12°、21.89±0.12°、22.68
Diffraction maximum, and salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 ° is had at ± 0.12 °.Especially, this diffraction pattern
6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22 ± 0.12 °, 13.78 ± 0.12 °,
14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、17.40±0.12°、18.62±
0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±0.12°、21.89±0.12°、22.68
± 0.12 °, 24.35 ± 0.12 °, 25.38 ± 0.12 °, 28.12 ± 0.12 °, 28.49 ± 0.12 °, have at 29.37 ± 0.12 °
Diffraction maximum.Especially, this diffraction pattern 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °,
13.22±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±
0.12°、17.40±0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65
±0.12°、21.89±0.12°、22.68±0.12°、24.35±0.12°、25.38±0.12°、28.12±0.12°、
28.49 ± 0.12 °, have diffraction maximum, and salt free ligands at 17.25 ± 0.12 ° and 17.65 ± 0.12 ° at 29.37 ± 0.12 °
Peak.
Embodiment 1: the crystallization (B crystal form) of formula I
(1) making fertile to be dissolved in toluene for western spit of fland free alkali 8g, (hydrobromic acid of 48% is water-soluble to add the hydrobromic acid of 1 equivalent
Liquid), stirring and crystallizing, leaching sediment, must irrigate for western spit of fland hydrobromate (93%)；
(2) make step (1) products therefrom 10g add in there-necked flask, add toluene 100g and water 10g, be heated to 85 DEG C and stir
After mixing dissolving, cooling crystallization, the crystallization of leaching is dried at a temperature of 60-70 DEG C, obtains hydrobromic acid fertile for Xi Ting (90%)；
(3) make step (2) products therefrom 1g add in there-necked flask, add acetone 12g, make at 55～60 DEG C of stirring 30min
Pulp thing, is then stirred at room temperature 1.5 hours, filters, gained crystallization vacuum drying, obtains the crystallization of referred to as B crystal form.
The powder x-ray diffraction figure such as accompanying drawing 1 of above-mentioned steps (3) gained crystallization, it presents crystallization spy of the present invention
Levy.
Embodiment 2: the crystallization (B crystal form) of formula I
(1) making fertile to be dissolved in toluene for western spit of fland free alkali 8g, (hydrobromic acid of 47% is water-soluble to add the hydrobromic acid of 1.05 equivalents
Liquid), stirring and crystallizing, leaching sediment, must irrigate for western spit of fland hydrobromate (91%)；
(2) make step (1) products therefrom 10g add in there-necked flask, add toluene 80g and water 8g, be heated to 85 DEG C of stirrings
After dissolving, cooling crystallization, the crystallization of leaching is dried at a temperature of 60-70 DEG C, obtains hydrobromic acid fertile for Xi Ting (92%)；
(3) make step (2) products therefrom 1g add in there-necked flask, add acetone 10g, make at 55～60 DEG C of stirring 20min
Pulp thing, is then stirred at room temperature 1 hour, filters, gained crystallization vacuum drying, obtains the crystallization of referred to as B crystal form.
The powder x-ray diffraction figure such as accompanying drawing 1 of above-mentioned steps (3) gained crystallization, it presents crystallization spy of the present invention
Levy.Comparing with diffraction angle value shown in Fig. 1, all differences of 23 diffraction maximums are less than 0.07 °, such as in Fig. 1 6.89 ° of display
Angle, the present embodiment gained B crystal form sample these 6.89 ° of angles ± 0.07 ° in the range of.
Embodiment 3: the crystallization (B crystal form) of formula I
(1) making fertile to be dissolved in toluene for western spit of fland free alkali 8g, (hydrobromic acid of 47% is water-soluble to add the hydrobromic acid of 0.95 equivalent
Liquid), stirring and crystallizing, leaching sediment, must irrigate for western spit of fland hydrobromate (92%)；
(2) make step (1) products therefrom 10g add in there-necked flask, add toluene 120g and water 12g, be heated to 85 DEG C and stir
After mixing dissolving, cooling crystallization, the crystallization of leaching is dried at a temperature of 60-70 DEG C, obtains hydrobromic acid fertile for Xi Ting (91%)；
(3) make step (2) products therefrom 1g add in there-necked flask, add acetone 15g, make at 55～60 DEG C of stirring 40min
Pulp thing, is then stirred at room temperature 2 hours, filters, gained crystallization vacuum drying, obtains the crystallization of referred to as B crystal form.
The powder x-ray diffraction figure such as accompanying drawing 1 of above-mentioned steps (3) gained crystallization, it presents crystallization spy of the present invention
Levy.Compare with diffraction angle value shown in Fig. 1, all differ less than 0.07 ° with corresponding 23 diffraction maximums, such as Fig. 1 shows
6.89 ° of angles, the present embodiment gained B crystal form sample these 6.89 ° of angles ± 0.07 ° in the range of.
Crystallization obtained as above, and hereafter gained various crystallinity material, its partial parameters measured according to the inventive method
Such as table 1 below.
Table 1:
| Sample/source | XRPD schemes | Water absorption (%) (x | Solubility (mg/ml) (y | Powder residual volume (%) (z |
| Embodiment 1 step 1 (β) | Same document (a | 0.74 | 1.11 | 4.35 |
| Embodiment 1 step 2 (β) | Same document (a | 0.63 | 1.22 | 3.16 |
| Embodiment 1 step 3 (B is brilliant) | Fig. 1 | 0.33 | 6.74 | 0.41 |
| Embodiment 2 step 1 (β) | Same document (a | 0.86 | 0.84 | 3.97 |
| Embodiment 2 step 2 (β) | Same document (a | 0.63 | 1.24 | 3.03 |
| Embodiment 2 step 3 (B is brilliant) | Same Fig. 1 (b | 0.27 | 8.35 | 0.27 |
| Embodiment 3 step 1 (β) | Same document (a | 0.83 | 0.96 | 4.24 |
| Embodiment 3 step 2 (β) | Same document (a | 0.67 | 1.16 | 3.34 |
| Embodiment 3 step 3 (B is brilliant) | Same Fig. 1 (b | 0.26 | 7.14 | 0.46 |
| Embodiment 11 (α is brilliant) | — | 0.41 | 1.93 | 4.22 |
| Embodiment 12 (β is brilliant) | Same document (a | 0.59 | 1.14 | 3.84 |
| Embodiment 13 (γ is brilliant) | — | 4.75 | 1.23 | 6.31 |
| Embodiment 14 | — | 1.24 | 2.11 | 3.73 |
| Embodiment 15 (β is brilliant) | — | 0.75 | 1.18 | 3.54 |
| Embodiment 16 (β is brilliant) | — | 0.63 | 1.06 | 3.75 |
| Embodiment 17 (β is brilliant) | — | 0.65 | 1.25 | 4.33 |
| Embodiment 18 (β is brilliant) | — | 0.59 | 1.21 | 3.96 |
Note:
A refers to identical with CN101472906B Fig. 3 with document, and has at 17.25 ± 0.12 ° and 17.65 ± 0.12 °
Diffraction maximum, and salt free ligands peak at 16.90 ± 0.12 ° and 17.40 ± 0.12 °；
B with Fig. 1 refer to the present invention appended by Fig. 1 essentially identical, and all differ with corresponding 23 diffraction maximums and be less than
0.07 °, and salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 °；
X water absorption refers to that sample is placed 5 hours under the relative humidity conditions of 90%, absorbs for weight of material
The percentage amounts of water；
Y solubility refers to concentration when sample reaches saturated in 25 ± 1 DEG C of water；
Z powder residual volume (%) is the result of the material using friability somascope of the present invention to measure, and reflects material
Absorption situation to chamber wall.
Embodiment 11: the crystallization (α is brilliant) of formula I
Prepare hydrobromic acid according to method shown in CN101472906B specification [0248]-[0251] section and irrigate the α type knot for Xi Ting
Brilliant.Its XRPD figure is identical with CN101472906B Fig. 2.
Embodiment 12: the crystallization (β is brilliant) of formula I
Prepare hydrobromic acid according to method shown in CN101472906B specification [0252]-[0256] section and irrigate the β type knot for Xi Ting
Brilliant.Its XRPD figure identical with CN101472906B Fig. 3, and 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °,
11.90±0.12°、13.22±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±
0.12°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±0.12°、21.89
±0.12°、22.68±0.12°、24.35±0.12°、25.38±0.12°、28.12±0.12°、28.49±0.12°、
There is diffraction maximum at 29.37 ± 0.12 °, at 17.25 ± 0.12 ° and 17.65 ± 0.12 °, have a diffraction maximum, but 16.90 ±
Salt free ligands peak at 0.12 ° and 17.40 ± 0.12 °.Through comparing, for β type crystallizes, except between 16.5 °～18.0 °
Outside there is an angle of diffraction at two peaks there were significant differences, the diffraction maximum of other position can fit like a glove.
It should be noted that in the present invention, when observing B crystal form of the present invention with known beta crystal difference, beta crystal is
At 17.25 ± 0.12 ° and 17.65 ± 0.12 °, be all respectively arranged with a diffraction maximum, but 16.90 ± 0.12 ° and 17.40 ±
Have no there is diffraction maximum at 0.12 ° simultaneously；And B crystal form is all to be respectively arranged with a diffraction at 16.90 ± 0.12 ° and 17.40 ± 0.12 °
Peak, but at 17.25 ± 0.12 ° and 17.65 ± 0.12 °, have no there is diffraction maximum simultaneously.This occur and/or simultaneously the most simultaneously
Occur that the phenomenon of diffraction maximum can overcome the impact of measure error, such as can overcome introduce for avoiding measure error permission ±
The situation of 0.12 °.Therefore, in any embodiment of either side of the present invention, the crystallization (i.e. B crystal form) of the present invention is 16.90
It is respectively arranged with a diffraction maximum at ± 0.12 ° and 17.40 ± 0.12 ° simultaneously, and/or at 17.25 ± 0.12 ° and 17.65 ± 0.12 °
Salt free ligands peak simultaneously.
Embodiment 13: the crystallization (γ is brilliant) of formula I
Prepare hydrobromic acid according to method shown in CN101472906B specification [0257]-[0260] section and irrigate the γ type knot for Xi Ting
Brilliant.Its XRPD figure is identical with CN101472906B Fig. 4.
Embodiment 14: the crystallization of formula I
With reference to the method for embodiment 1, except for the difference that cancel step therein (2), it may be assumed that
(1) making fertile to be dissolved in toluene for western spit of fland free alkali 8g, (hydrobromic acid of 48% is water-soluble to add the hydrobromic acid of 1 equivalent
Liquid), stirring and crystallizing, leaching sediment, must irrigate for western spit of fland hydrobromate (93%)；
(2) make step (1) products therefrom 1g add in there-necked flask, add acetone 12g, make at 55～60 DEG C of stirring 30min
Pulp thing, is then stirred at room temperature 1.5 hours, filters, gained crystallization vacuum drying, the crystallization obtained.
After measured, the powder x-ray diffraction figure of above-mentioned steps (2) gained crystallization had both been different from Fig. 1 of the present invention, the most not
Be same as Fig. 3 of CN101472906B, particularly, wherein similar in appearance to or be similar to 6.89 ° with Fig. 1 of the present invention, 9.73 °,
13.78 °, 14.62 °, 16.90 °, six diffraction maximums at 17.40 °, their angle of diffraction 2 θ value all reduces more than 0.35 °,
All reducing 0.35～0.70 °, such as the present embodiment 14 gained end-product crystallization has one at 2 θ=6.43 ° and is similar to this
Diffraction maximum at 6.89 ° in bright Fig. 1,2 θ at this peak are on duty correspondingly reduces 0.46 °.
Anticipate without toluene/water before carrying out acetone treatment if visible, it is difficult to obtain the B crystal form of the present invention.
Embodiment 15: the crystallization (β is brilliant) of formula I
With reference to the method for embodiment 1, except for the difference that toluene is used to replace in the acetone in step (3), the crystallization obtained.
After measured, gained crystallization is identical with Fig. 3 of CN101472906B, particularly at 6.89 ° ± 0.12 °, 9.73 °
± 0.12 °, 13.78 ° ± 0.12 °, 14.62 ° ± 0.12 °, 17.25 ° ± 0.12 °, show six β types at 17.65 ° ± 0.12 °
The typical diffractive peak of crystallization, and salt free ligands peak at 16.90 ± 0.12 ° and 17.40 ± 0.12 °.
Embodiment 16: the crystallization (β is brilliant) of formula I
With reference to the method for embodiment 1, except for the difference that toluene-water (10:1, v/v) is used to replace in the acetone in step (3),
The crystallization obtained.
After measured, gained crystallization is identical with Fig. 3 of CN101472906B, particularly at 6.89 ° ± 0.12 °, 9.73 °
± 0.12 °, 13.78 ° ± 0.12 °, 14.62 ° ± 0.12 °, 17.25 ° ± 0.12 °, show six β types at 17.65 ° ± 0.12 °
The typical diffractive peak of crystallization, and salt free ligands peak at 16.90 ± 0.12 ° and 17.40 ± 0.12 °.
Embodiment 17: the crystallization (β is brilliant) of formula I
With reference to the method for embodiment 1, except for the difference that dimethylbenzene is used to replace in the acetone in step (3), the crystallization obtained.
After measured, gained crystallization is identical with Fig. 3 of CN101472906B, particularly at 6.89 ° ± 0.12 °, 9.73 °
± 0.12 °, 13.78 ° ± 0.12 °, 14.62 ° ± 0.12 °, 17.25 ° ± 0.12 °, show six β types at 17.65 ° ± 0.12 °
The typical diffractive peak of crystallization, and salt free ligands peak at 16.90 ± 0.12 ° and 17.40 ± 0.12 °.
Embodiment 18: the crystallization (β is brilliant) of formula I
With reference to the method for embodiment 1, except for the difference that ethyl acetate is used to replace in the acetone in step (3), the knot obtained
Brilliant.
After measured, gained crystallization is identical with Fig. 3 of CN101472906B, particularly at 6.89 ° ± 0.12 °, 9.73 °
± 0.12 °, 13.78 ° ± 0.12 °, 14.62 ° ± 0.12 °, 17.25 ° ± 0.12 °, show six β types at 17.65 ° ± 0.12 °
The typical diffractive peak of crystallization, and salt free ligands peak at 16.90 ± 0.12 ° and 17.40 ± 0.12 °.
Test example 1: the chemical stability after various materials and auxiliary material combination
By the compound of formula I of the different crystal forms of gained above, mix by the way of being fully ground with different amounts of sugar
Closing, the mixture vial obtained seals, and is placed in 40 DEG C of insulating boxs placement 5 months, uses HPLC method of the present invention
Measure each sample total impurities content (deduction solvent and auxiliary material peak) when 0 month and May.For each sample, it is calculated as follows 5
Total impurities increments (%) during the moon:
Total impurities increments (%)=[(0 month total impurities content of total impurities content in May) 0 month total impurities content of ÷] ×
100%
This total impurities increments (%) shows that the most greatly sample impurity increase during long-term storage is the fastest.
Gained crystallization above is combined with different amounts of different sugar, measures the most miscellaneous after high-temperature treatment May of these combinations
Matter increments (%), result such as table 2 below.
Table 2:
| Activating agent | Lactose | Mannitol | Lactose+mannitol (1:1) | Total impurities increments (%) |
| Embodiment 1 step 2 (β) | ×10 | 177 | ||
| Embodiment 1 step 2 (β) | ×10 | 215 | ||
| Embodiment 1 step 3 (B is brilliant) | ×1 | 42 | ||
| Embodiment 1 step 3 (B is brilliant) | ×10 | 34 | ||
| Embodiment 1 step 3 (B is brilliant) | ×30 | 39 | ||
| Embodiment 1 step 3 (B is brilliant) | ×1 | 35 | ||
| Embodiment 1 step 3 (B is brilliant) | ×10 | 42 | ||
| Embodiment 1 step 3 (B is brilliant) | ×30 | 29 | ||
| Embodiment 1 step 3 (B is brilliant) | ×5 | 36 | ||
| Embodiment 1 step 3 (B is brilliant) | ×20 | 40 | ||
| Embodiment 2 step 3 (B is brilliant) | ×5 | 27 | ||
| Embodiment 2 step 3 (B is brilliant) | ×20 | 33 | ||
| Embodiment 2 step 3 (B is brilliant) | ×5 | 38 | ||
| Embodiment 2 step 3 (B is brilliant) | ×20 | 29 | ||
| Embodiment 2 step 3 (B is brilliant) | ×10 | 40 | ||
| Embodiment 3 step 3 (B is brilliant) | ×10 | 33 | ||
| Embodiment 3 step 3 (B is brilliant) | ×10 | 27 |
| Embodiment 3 step 3 (B is brilliant) | ×10 | 38 | ||
| Embodiment 11 (α is brilliant) | ×10 | 194 | ||
| Embodiment 11 (α is brilliant) | ×10 | 225 | ||
| Embodiment 11 (α is brilliant) | ×10 | 184 | ||
| Embodiment 12 (β is brilliant) | ×10 | 206 | ||
| Embodiment 12 (β is brilliant) | ×10 | 179 | ||
| Embodiment 12 (β is brilliant) | ×10 | 193 | ||
| Embodiment 13 (γ is brilliant) | ×10 | 197 | ||
| Embodiment 13 (γ is brilliant) | ×10 | 223 | ||
| Embodiment 13 (γ is brilliant) | ×10 | 204 |
In table in the column of various sugar, when " × 5 ", " × 10 " represent this sugar and compound of formula I combination mixture, the weight of sugar
It it is the multiple of compound of formula I weight；Such as, when embodiment 1 step 2 (β) crystallization combines mixture with lactose in " × 5 " mode, it is
Refer to the activating agent of 1 weight portion and the lactose mixing of 5 weight portions.
Table 2 result shows, when B crystal form combines with carbohydrate, it increases inconspicuous at high-temperature treatment rear impurity, but other
Crystal formation significantly increases at high-temperature treatment rear impurity when combining with lactose and/or mannitol.
In other complementary testing, with reference to the method for above table 2 acquired results, embodiment 1 step 3 (B crystal form), enforcement
Example 11 (crystallization of α type), embodiment 12 (crystallization of β type), embodiment 13 (crystallization of γ type) do not mix with carbohydrate, but after directly sealing
Carrying out high-temperature treatment, after May, the total impurities increments of four kinds of samples is all more than 145%, all in the range of 145～188%.
In other complementary testing, with reference to the method for above table 2 acquired results, make embodiment 1,2,3 gained B crystallization point
Time not with 5 times of weight or the sorbierite of 15 times of weight or sucrose combination, composition is after high-temperature treatment, and total impurities increments is equal
More than 157%, all in the range of 157～236%, display is the sorbierite of carbohydrate equally or sucrose can not suppress miscellaneous effectively
Matter gathers way.To this end, in one embodiment of the invention, it is provided that carbohydrate (it is lactose and/or mannitol) is in system
Purposes in the medicine of the standby compound of formula I crystallization comprising either side any embodiment of the present invention, wherein said carbohydrate makes
Impurity gathers way and is suppressed.In one embodiment, described carbohydrate makes impurity gather way to be able to suppression and refer to, contained
Total impurities increments when the medicine of described crystallization and carbohydrate is placed 5 months in 40 DEG C of insulating boxs is less than 100%, e.g., less than
75%, e.g., less than 50%.
Test example 2: the study on the stability of tablet
Typical tablet prescription:
Prescription 1: compound of formula I (with free base) 10mg, lactose 40mg, starch 20mg, copolyvidone 4mg, crystallite are fine
Dimension element 20mg, croscarmellose sodium 4mg, magnesium stearate 2mg.
Prescription 2: compound of formula I (with free base) 10mg, mannitol 35mg, starch 20mg, copolyvidone 5mg, crystallite
Cellulose 25mg, sodium starch glycollate 3mg, magnesium stearate 2mg.
Prescription 3: compound of formula I (with free base) 10mg, starch 50mg, copolyvidone 4mg, microcrystalline cellulose 30mg,
Croscarmellose sodium 4mg, magnesium stearate 2mg.
Typical tablet preparation method: compound of formula I, carbohydrate (prescription 1,2 adds, and is not added with in prescription 3), starch, copolyvidone are existed
Impeller speed be 1000rpm high shear mixers in mix 2 minutes；Then, the speed of impeller is down to 800rpm, and
Adding appropriate (solid material about 8% weight) water in 1 minute, the wet granular processed carried out 7 minutes processes；Wet granular is made to be dried, mistake
The 16 whole grains of mesh sieve；Gained particle mixes with microcrystalline cellulose and disintegrant, then mixes with magnesium stearate, obtains the most mixed
Grain；This end is mixed on tablet press machine and carries out compressing tablet, obtain every and contain the compound of formula I tablet with free base 10mg.[additionally,
As required, it is also possible to by adjusting the punch die size of tablet press machine, it is thus achieved that there is the tablet of different amounts of reactive compound, such as
Obtain every tablet of tablet containing the free alkali of 2.5,5,10,20,25,30,40,50,60 or 80mg]
Use above typical case's prescription 1,2,3, and use the compound of formula I of different crystal form, obtain different tablets, will
These tablets pack, and the method for reference test example 1 makes them dispose 5 months at 40 DEG C, measures and calculate each tablet
The total impurities increments (%) of sample.Result such as table 3 below.
Table 3:
| Activating agent+prescription | Total impurities increments (%) | Activating agent+prescription | Total impurities increments (%) |
| Embodiment 1 step 3 (B is brilliant)+prescription 1 | 52 | Embodiment 11 (α is brilliant)+prescription 1 | 187 |
| Embodiment 1 step 3 (B is brilliant)+prescription 2 | 46 | Embodiment 11 (α is brilliant)+prescription 2 | 204 |
| Embodiment 1 step 3 (B is brilliant)+prescription 3 | 157 | Embodiment 11 (α is brilliant)+prescription 3 | 183 |
| Embodiment 2 step 3 (B is brilliant)+prescription 1 | 47 | Embodiment 12 (β is brilliant)+prescription 1 | 202 |
| Embodiment 2 step 3 (B is brilliant)+prescription 2 | 43 | Embodiment 12 (β is brilliant)+prescription 2 | 175 |
| Embodiment 2 step 3 (B is brilliant)+prescription 3 | 178 | Embodiment 12 (β is brilliant)+prescription 3 | 198 |
| Embodiment 3 step 3 (B is brilliant)+prescription 1 | 57 | Embodiment 13 (γ is brilliant)+prescription 1 | 217 |
| Embodiment 3 step 3 (B is brilliant)+prescription 2 | 43 | Embodiment 13 (γ is brilliant)+prescription 2 | 203 |
| Embodiment 3 step 3 (B is brilliant)+prescription 3 | 212 | Embodiment 13 (γ is brilliant)+prescription 3 | 194 |
Additionally, the dissolution rate of 18 the tablet samples determined in above table 3.Specifically, according to Chinese Pharmacopoeia version in 2010
In two annex XC dissolution methods, contained the second method i.e. paddle method is carried out, and solvent is 900ml water, to dissolution during 30min
Degree, the dissolution rate of 9 kinds of tablets that the tri-kinds of Type B crystallizations of result display embodiment 1-3 prepare is all in 90%～100% scope
In, the very gratifying dissolving out capability of display；And 9 kinds of tablets that the tri-kinds of not syncrystallizations of embodiment 11-13 prepare is molten
Out-degree is all in the range of 55%～72%, and dissolving out capability is unsatisfactory, and (this area usually requires that dissolution rate with this understanding
Reach the degree of 75%).
Embodiment 1 step 3 (B is brilliant), embodiment 11 (α is brilliant), embodiment 12 (β is brilliant), four kinds of crystallizations of embodiment 13 (γ is brilliant)
When using prescription 1 to prepare tablet, after finally mixing with magnesium stearate, discharge the material in mixer, scrape inner wall of mixer
Residual powder, measure the content (being converted to free base) of active component in these powder.Result: embodiment 1 step 3 (B
Brilliant) content of active component is 10.07% in powder, it coincide with theoretical mixed material inputting ratio rate, show that active component is the most substantially
Sticking tendency；In embodiment 11 (α is brilliant) powder, the content of active component is 17.74%, lives in embodiment 12 (β is brilliant) powder
Property composition content be 15.37%, in embodiment 13 (γ is brilliant) powder, the content of active component is 14.68%, shows three kinds of things
In material active component have significantly adhere to tendency.
Tablet preparation example 1:
Irrigate for Xi Ting as active component with the B crystal form hydrobromic acid that the embodiment of the present invention 1 method prepares, with reference to trying above
Test " typical tablet preparation method " described in example 2 preparation have following formula tablet (represent formula with the mg amount of each composition in every,
Every batch of preparation amount is 10,000, and the amount of active component represents with the amount of free alkali):
Formula 1:B crystal formation 10mg, lactose 45mg, starch 22mg, copolyvidone 4mg, microcrystalline cellulose 20mg, crosslinking hydroxyl first
Sodium cellulosate 3mg, magnesium stearate 1mg.
Formula 2:B crystal formation 20mg, lactose 35mg, starch 20mg, copolyvidone 4mg, microcrystalline cellulose 20mg, crosslinking hydroxyl first
Sodium cellulosate 4mg, magnesium stearate 1mg.
Formula 3:B crystal formation 1mg, lactose 45mg, starch 22mg, copolyvidone 3mg, microcrystalline cellulose 23mg, crosslinking hydroxyl first
Sodium cellulosate 3mg, magnesium stearate 1mg.
Formula 4:B crystal formation 20mg, mannitol 35mg, starch 10mg, copolyvidone 3mg, microcrystalline cellulose 25mg, hydroxyl second
Acid-starch sodium 3mg, magnesium stearate 0.5mg.
Formula 5:B crystal formation 10mg, mannitol 37mg, starch 20mg, copolyvidone 3mg, microcrystalline cellulose 25mg, hydroxyl second
Acid-starch sodium 4mg, magnesium stearate 1mg.
Formula 6:B crystal formation 30mg, mannitol 28mg, starch 15mg, copolyvidone 3mg, microcrystalline cellulose 25mg, hydroxyl second
Acid-starch sodium 4mg, magnesium stearate 0.5mg.
Formula 7:B crystal formation 2mg, mannitol 40mg, starch 20mg, copolyvidone 3mg, microcrystalline cellulose 26mg, hydroxyl second
Acid-starch sodium 4mg, magnesium stearate 0.5mg.
Formula 8:B crystal formation 10mg, mannitol 45mg, microcrystalline cellulose 30mg, hydroxypropyl cellulose 10mg, hydroxyacetic acid form sediment
Powder sodium 4mg, magnesium stearate 1mg.
Inventor attempts above-mentioned eight kinds of tablets of formula 1-8 gained are carried out powder x-ray diffraction detection, and result is at diffraction
Collection of illustrative plates shows: at 6.89 ± 0.12 °, 9.73 ± 0.12 °, 13.78 ± 0.12 ° and 14.62 ± 0.12 °, have diffraction maximum；?
Salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 °；Diffraction maximum is had at 16.90 ± 0.12 ° and 17.40 ± 0.12 °；
6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22 ± 0.12 °, 13.78 ± 0.12 °,
14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、17.40±0.12°、18.62±
0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±0.12°、21.89±0.12°、22.68
± 0.12 °, 24.35 ± 0.12 °, 25.38 ± 0.12 °, 28.12 ± 0.12 °, 28.49 ± 0.12 °, energy at 29.37 ± 0.12 °
Enough find diffraction maximum.
By filling a prescription above, eight kinds of tablets of 1-8 gained detect as follows:
Dissolution rate detection (method is as described herein), result shows that the dissolution rate when 30min all reaches more than 87%；
Study on the stability: pack, places 6 months at 40 DEG C, and the residual volume of active component is equal > 97% (this area
Usually require that 90%).
Claims (46)
1. with the crystallization of compounds of Formula I
I,
Its use Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, 6.89 ± 0.12 °, 8.42 ±
0.12°、9.73±0.12°、11.90±0.12°、13.22±0.12°、13.78±0.12°、14.62±0.12°、15.67±
0.12°、16.12±0.12°、16.90±0.12°、17.40°、18.62±0.12°、18.95±0.12°、19.46±
0.12°、20.08±0.12°、20.65±0.12°、21.89±0.12°、22.68±0.12°、24.35±0.12°、25.38
± 0.12 °, 28.12 ± 0.12 °, 28.49 ± 0.12 °, have diffraction maximum at 29.37 ± 0.12 °, and at 17.25 ± 0.12 ° and
Salt free ligands peak at 17.65 ± 0.12 °.
Crystallization the most according to claim 1, it uses Cu-K α radiation, has powder x-ray diffraction substantially as shown in
Collection of illustrative plates.
3. with the crystallization of compounds of Formula I
I,
It is placed 5 hours under the relative humidity conditions of 90%, absorbs the amount of water less than 1%；
It uses Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles,
6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22 ± 0.12 °, 13.78 ±
0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、17.40°、18.62±
0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±0.12°、21.89±0.12°、22.68
± 0.12 °, 24.35 ± 0.12 °, 25.38 ± 0.12 °, 28.12 ± 0.12 °, 28.49 ± 0.12 °, have at 29.37 ± 0.12 °
Diffraction maximum, and salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 °.
Crystallization the most according to claim 3, it uses Cu-K α radiation, has powder x-ray diffraction substantially as shown in
Collection of illustrative plates.
Crystallization the most according to claim 3, it places 5 hours under the relative humidity conditions of 90%, and the amount absorbing water is less than
0.75%。
Crystallization the most according to claim 3, it places 5 hours under the relative humidity conditions of 90%, and the amount absorbing water is less than
0.5%。
7. with the crystallization of compounds of Formula I
I,
When it reaches saturated in the water of 25 ± 1 ° of C, the concentration of this saturated solution compounds of formula I is more than 2mg/ml；It uses Cu-
K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ±
0.12°、11.90±0.12°、13.22±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12
±0.12°、16.90±0.12°、17.40°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±
0.12°、20.65±0.12°、21.89±0.12°、22.68±0.12°、24.35±0.12°、25.38±0.12°、28.12
± 0.12 °, 28.49 ± 0.12 °, have diffraction maximum at 29.37 ± 0.12 °, and at 17.25 ± 0.12 ° and 17.65 ± 0.12 °
Salt free ligands peak, place.
Crystallization the most according to claim 7, it uses Cu-K α radiation, has powder x-ray diffraction substantially as shown in
Collection of illustrative plates.
Crystallization the most according to claim 7, when it reaches saturated in the water of 25 ± 1 ° of C, this saturated solution compounds of formula I dense
Degree is more than 3mg/ml.
Crystallization the most according to claim 7, when it reaches saturated in the water of 25 ± 1 ° of C, this saturated solution compounds of formula I
Concentration is more than 4mg/ml.
11. crystallizations according to claim 7, when it reaches saturated in the water of 25 ± 1 ° of C, this saturated solution compounds of formula I
Concentration is more than 5mg/ml.
12. crystallizations according to claim 7, when it reaches saturated in the water of 25 ± 1 ° of C, this saturated solution compounds of formula I
Concentration is 2 ~ 10 mg/ml.
13. crystallizations according to claim 7, when it reaches saturated in the water of 25 ± 1 ° of C, this saturated solution compounds of formula I
Concentration is 3 ~ 10 mg/ml.
14. crystallizations according to claim 7, when it reaches saturated in the water of 25 ± 1 ° of C, this saturated solution compounds of formula I
Concentration is 4 ~ 10 mg/ml.
15. crystallizations according to claim 7, when it reaches saturated in the water of 25 ± 1 ° of C, this saturated solution compounds of formula I
Concentration is 5 ~ 10 mg/ml.
16. with the crystallization of compounds of Formula I
I,
During its size-reduced one-tenth fine powder, this fine powder disposes 5 with the rotational speed of every point of kind 25 ± 1 turns in friability somascope
After minute, the powder residual volume at friability somascope inwall is less than 2%；It uses Cu-K α radiation, represent with 2 θ angles
In powder x-ray diffraction collection of illustrative plates, 6.89 ± 0.12 °, 8.42 ± 0.12 °, 9.73 ± 0.12 °, 11.90 ± 0.12 °, 13.22
±0.12°、13.78±0.12°、14.62±0.12°、15.67±0.12°、16.12±0.12°、16.90±0.12°、
17.40°、18.62±0.12°、18.95±0.12°、19.46±0.12°、20.08±0.12°、20.65±0.12°、21.89
±0.12°、22.68±0.12°、24.35±0.12°、25.38±0.12°、28.12±0.12°、28.49±0.12°、
Diffraction maximum, and salt free ligands peak at 17.25 ± 0.12 ° and 17.65 ± 0.12 ° is had at 29.37 ± 0.12 °.
17. crystallizations according to claim 16, it uses Cu-K α radiation, has powder X-ray substantially as shown in and spread out
Penetrate collection of illustrative plates.
18. crystallizations according to claim 16, during its size-reduced one-tenth fine powder, this fine powder in friability somascope with every point
After the rotational speed of kind 25 ± 1 turns disposes 5 minutes, the powder residual volume at friability somascope inwall is less than 1.5%.
19. crystallizations according to claim 16, during its size-reduced one-tenth fine powder, this fine powder in friability somascope with every point
After the rotational speed of kind 25 ± 1 turns disposes 5 minutes, the powder residual volume at friability somascope inwall is less than 1%.
20. crystallizations according to claim 16, during its size-reduced one-tenth fine powder, this fine powder in friability somascope with every point
After the rotational speed of kind 25 ± 1 turns disposes 5 minutes, the powder residual volume at friability somascope inwall is less than 0.75%.
21. crystallizations according to claim 16, during its size-reduced one-tenth fine powder, this fine powder in friability somascope with every point
After the rotational speed of kind 25 ± 1 turns disposes 5 minutes, the powder residual volume at friability somascope inwall is less than 0.5%.
The method of the crystallization of 22. preparation any one of claim 1-21, it comprises the steps:
(1) make to irrigate to be dissolved in toluene for western spit of fland free alkali compound 1-[2-(2,4-3,5-dimethylphenyl sulfenyl) phenyl] piperazine, add
Enter the hydrobromic acid of 0.95 ~ 1.05 equivalent, stirring and crystallizing, leaching sediment, must irrigate for western spit of fland hydrobromate；
(2) make step (1) products therefrom 1 weight portion add in there-necked flask, add toluene 8 ~ 12 weight portion and water 0.8 ~ 1.2 weight
Part, after being heated to 85 ° of C stirring and dissolving, cooling crystallization, the crystallization of leaching is dried at a temperature of 60-70 ° of C, obtains hydrobromic acid fertile for west
Spit of fland；
(3) make step (2) products therefrom 1 weight portion add in there-necked flask, add acetone 10 ~ 15 weight portion, stir at 55 ~ 60 ° of C
20 ~ 40min makes pulp thing, is then stirred at room temperature 1 ~ 2 hour, filters, gained crystallization vacuum drying, is crystallized.
23. 1 kinds of pharmaceutical compositions, wherein comprise in crystal form described in any one of claim 1-21 with following formula I chemical combination
Thing, and pharmaceutic adjuvant
I。
24. pharmaceutical compositions according to claim 23, wherein said pharmaceutic adjuvant includes the sugar that can use as diluent
Class.
25. pharmaceutical compositions according to claim 24, wherein said carbohydrate is selected from: lactose, mannitol, sorbierite, sucrose.
26. pharmaceutical compositions according to claim 24, wherein said carbohydrate is selected from: lactose, mannitol.
27. pharmaceutical compositions according to claim 24, wherein comprise the described crystallization of 10 weight portions, and 10 ~ 1000 weight
The described carbohydrate of part.
28. pharmaceutical compositions according to claim 24, wherein comprise the described crystallization of 10 weight portions, and 10 ~ 500 weight portions
Described carbohydrate.
29. pharmaceutical compositions according to claim 24, wherein comprise the described crystallization of 10 weight portions, and 10 ~ 300 weight portions
Described carbohydrate.
30. pharmaceutical compositions according to claim 23, it is oral solid formulation.
31. pharmaceutical compositions according to claim 23, it is tablet, capsule or granule.
32. pharmaceutical compositions according to claim 23, the most also comprise selected from following auxiliary material: in addition to described carbohydrate
Diluent, disintegrant, adhesive, lubricant.
33. according to the pharmaceutical composition of claim 32, and wherein said diluent is selected from: starch, microcrystalline cellulose, phosphoric acid hydrogen
Calcium.
34. according to the pharmaceutical composition of claim 33, and described diluent accounts for the 10 ~ 90% of composition total weight.
35. according to the pharmaceutical composition of claim 33, and described diluent accounts for the 20 ~ 80% of composition total weight.
36. according to the pharmaceutical composition of claim 32, and wherein said disintegrant is selected from: sodium starch glycolate, PVPP,
Croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose.
37. according to the pharmaceutical composition of claim 36, and described disintegrant accounts for the 2 ~ 10% of composition total weight.
38. according to the pharmaceutical composition of claim 36, and described disintegrant accounts for the 2 ~ 7% of composition total weight.
39. according to the pharmaceutical composition of claim 32, and wherein said adhesive is selected from: hydroxypropyl methyl cellulose, polyethylene
Pyrrolidones.
40. according to the pharmaceutical composition of claim 39, and described adhesive accounts for the 2 ~ 10% of composition total weight.
41. according to the pharmaceutical composition of claim 39, and described adhesive accounts for the 2 ~ 5% of composition total weight.
42. according to the pharmaceutical composition of claim 32, and wherein said lubricant is selected from: stearic acid, magnesium stearate, talcum powder,
PEG4000~8000。
43. according to the pharmaceutical composition of claim 42, and described lubricant accounts for the 1 ~ 10% of composition total weight.
44. according to the pharmaceutical composition of claim 42, and described lubricant accounts for the 1 ~ 5% of composition total weight.
Purposes in the medicine that the compound of formula I that 45. carbohydrates comprise any one of claim 1-21 in preparation crystallizes, wherein said
Carbohydrate makes impurity gather way to be suppressed, and described carbohydrate is lactose and/or mannitol.
The compound of formula I crystallization of 46. any one of claim 1-21 is used for preventing or treat central nervous system in preparation and is correlated with
Disease medicine in purposes.
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| CN104447622B (en) * | 2014-11-28 | 2017-01-04 | 郑州大明药物科技有限公司 | Hydrobromic acid irrigates the preparation method for western spit of fland beta crystal |
| CN106279065A (en) * | 2015-05-12 | 2017-01-04 | 北京深蓝海生物医药科技有限公司 | A kind of hydrobromic acid irrigates the refined rotating crystal method for Xi Ting |
| CN104910099B (en) * | 2015-05-22 | 2017-03-08 | 扬子江药业集团有限公司 | The preparation method for western spit of fland crystal irrigated by a kind of hydrobromic acid |
| CN106279066A (en) * | 2015-05-22 | 2017-01-04 | 天津药物研究院有限公司 | A kind of hydrobromic acid irrigates the purification process for western spit of fland crystal |
| CN105380921B (en) * | 2015-12-15 | 2017-06-09 | 中山万汉制药有限公司 | A kind of preparation method of hydrobromic acid Vortioxetine piece |
| US20190194154A1 (en) * | 2016-01-20 | 2019-06-27 | Amneal Pharmaceuticals Company Gmbh | Polymorphic Forms Of Vortioxetine Hydrobromide Tert-Butanolate |
| CN107789327B (en) * | 2016-09-07 | 2020-06-02 | 成都康弘药业集团股份有限公司 | Pharmaceutical composition containing vortioxetine hydrobromide and preparation method thereof |
| CN107843656B (en) * | 2016-09-21 | 2021-02-26 | 成都弘达药业有限公司 | Detection method of 2, 4-dimethylthiophenol related substances |
| CN108069924A (en) * | 2016-11-11 | 2018-05-25 | 浙江京新药业股份有限公司 | The preparation method of Vortioxetine hydrobromate alpha-crystal form |
| CN108069925A (en) * | 2016-11-16 | 2018-05-25 | 浙江京新药业股份有限公司 | Vortioxetine hydrobromate anhydrous crystal forms I and its preparation method and application |
| CN108929287A (en) * | 2017-05-26 | 2018-12-04 | 万全万特制药江苏有限公司 | The purification of Vortioxetine |
| CN111728973A (en) * | 2020-05-27 | 2020-10-02 | 中国医学科学院病原生物学研究所 | Medicine for resisting novel coronavirus SARS-CoV-2 and its application |
| CN112125868B (en) * | 2020-09-25 | 2021-08-03 | 中山万远新药研发有限公司 | Crystal form of vortioxetine hydrobromide, preparation method, composition and application thereof |
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