WO2018076245A1 - Crystal of bis(8-quinolinamine) derivatives - Google Patents

Crystal of bis(8-quinolinamine) derivatives Download PDF

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Publication number
WO2018076245A1
WO2018076245A1 PCT/CN2016/103606 CN2016103606W WO2018076245A1 WO 2018076245 A1 WO2018076245 A1 WO 2018076245A1 CN 2016103606 W CN2016103606 W CN 2016103606W WO 2018076245 A1 WO2018076245 A1 WO 2018076245A1
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crystal
bis
butyl
quinolinamine
imino
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PCT/CN2016/103606
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French (fr)
Inventor
Jing Li
Guixing Deng
Mingjie Sun
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Guangzhou Welman New Drug R&D Co., Ltd.
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Priority to PCT/CN2016/103606 priority Critical patent/WO2018076245A1/en
Publication of WO2018076245A1 publication Critical patent/WO2018076245A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/40—Nitrogen atoms attached in position 8

Definitions

  • the present invention relates to a crystal of bis (8-quinolinamine) derivatives, a composition and use thereof, particularly relates to a crystal of the compound of N-butyl-2, 2’-imino-bis (8-quinolinamine) , a composition and use thereof.
  • N-butyl-2, 2’-imino-bis (8-quinolinamine) (compound A) is a multiple quinolines compound.
  • US8324196 discloses that bis (8-substituted quinoline) derivatives including compound A are metal ion chelators, which can effectively reduce the accumulation of metal ions in the body.
  • the accumulation of the metal ions such as Na + , K + , Ca 2+ , Cu 2+ , Zn 2+ , Fe 3+ , Al 3+ and the like can damage the relevant neuron cells of brain or spinal cord, and bring about a series of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) , spinal muscular atrophy, ataxia telangiectasia, Creutzfeldt-Jakob disease, Huntington's disease, spinocerebellar ataxia, multiple sclerosis (MS) , Parkinson's disease, Alzheimer's disease (AD) , primary lateral sclerosis (PLS) and the like.
  • ALS amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • MS multiple sclerosis
  • AD Alzheimer's disease
  • PLS primary lateral sclerosis
  • metal ions with a high concentration can promote the accumulation of beta-amyloid protein, and induce the Tau protein to form a neurofibrillary tangle (NFT) ; while the two pathological changes of Alzheimer's disease (AD) are just the accumulation of beta-amyloid proteins outside the brain nervous cell and the neurofibrillary tangles formed by the hyperphosphorylation of Tau protein inside the nervous cell ( “Chinese Journal of Difficult and Complicated Cases” , 2015, 14 (3) , p319-322) .
  • US8324196 discloses a preparation method of compound A, comprising: catalytic hydrogenating the corresponding nitroquinoline derivatives to obtain crude product, and then dissolving the crude product in dichloromethane, and adding n-hexane to precipitate, thereby a brown powder is obtained.
  • the prior literature discloses a coordination compound formed of compound A and metallic copper ion, and the crystal structure of the coordination compound.
  • the spatial structure shows that copper ions bond to four nitrogen atoms in the two aminoquinolines of compound A, forming a stable crystal structure, and there are eight molecules of coordination compounds in one unit cell (see “European Journal of Inorganic Chemistry” , 2008, 36, p5622-5631) .
  • the change of the molecule microcosmic spatial structure may affect the property of the compound itself.
  • Many studies on the coordination compound formed by the complexation of compound A and metal copper ion have been carried out in the prior art, however, there is no study on the crystallography of the compound A itself.
  • the purpose of the present invention is to provide a crystal of N-butyl-2, 2’-imino-bis (8-quinolinamine) , preparation method and use thereof.
  • the present invention further provides a composition containing the above-mentioned crystal of N-butyl-2, 2’-imino-bis (8-quinolinamine) and use thereof.
  • N-butyl-2, 2’-imino-bis (8-quinolinamine) is a known compound.
  • the inventors when making improvement on the preparation method of the compound, the inventors surprisingly found that the product exists in a new form –crystal, i.e., N-butyl-2, 2’-imino-bis (8-quinolinamine) in the form of crystal (or called the crystal of N-butyl-2, 2’-imino-bis (8-quinolinamine) ) .
  • the crystal refers to a substance formed by the regularly periodic repeated arrangement of the atoms, molecules and/or ions of compound in the space.
  • the crystal is an orderly arrangement of the molecules of the substance; it has a significant difference in microstructure compared with the disordered arrangement such as amorphous arrangement.
  • the crystal can be characterized by powder X-ray diffraction analysis method.
  • ⁇ angle is also called grazing angle, it is an angle between the incident ray and the crystal plane of the crystal.
  • the X-ray at a specific grazing angle may be diffracted between certain crystal planes of the crystal when passing through the crystal, and it presents characteristic peaks (of which the intensity is greater than the noise) in the obtained spectrum.
  • the 2 ⁇ (diffraction angle) angle or the interplanar spacing (the distance between the crystal planes of the crystal substance) of the characteristic peaks can characteristically characterize the spatial structure of the crystal, and it can be distinguished from the existing forms of existence.
  • the crystal of N-butyl-2, 2’-imino-bis (8-quinolinamine) can be characterized by powder X-ray diffraction analysis.
  • the crystal of N-butyl-2, 2’-imino-bis (8-quinolinamine) may comprise one or more characteristic peaks represented by the following 2 ⁇ angles in the powder X-ray diffraction spectrum: 6.70° ⁇ 0.2°, 12.35° ⁇ 0.2°, 13.75° ⁇ 0.2°, 15.81° ⁇ 0.2° and 19.72° ⁇ 0.2°.
  • the crystal of N-butyl-2, 2’-imino-bis (8-quinolinamine) according to the present invention may comprise one or more characteristic peaks represented by the following interplanar spacings in the powder X-ray diffraction spectrum:
  • the peaks with low 2 ⁇ angle, high interplanar spacing, clear and integral shape and high strength tend to better reflect the characteristics of the crystal.
  • the parameters of the single characteristic peaks such as peak height, peak area and the like, tend to not have characteristics, and cannot be used alone to characterize the crystal.
  • the powder X-ray diffraction spectrum of the crystal can further comprise one or more characteristic peaks represented by the following 2 ⁇ angles: 11.02° ⁇ 0.2°, 17.02° ⁇ 0.2°, 17.60° ⁇ 0.2°, 19.00° ⁇ 0.2°, 21.15° ⁇ 0.2° and 22.12° ⁇ 0.2°; correspondingly, the powder X-ray diffraction spectrum of the crystal can further comprise one or more characteristic peaks represented by the following interplanar spacings: and In a more preferable embodiment, the powder X-ray diffraction spectrum of the crystal can further comprise one or more characteristic peaks represented by the following 2 ⁇ angles: 22.79° ⁇ 0.2°, 24.91° ⁇ 0.2° and 27.12° ⁇ 0.2°; correspondingly, the powder X-ray diffraction spectrum of the crystal can further comprise one or more characteristic peaks represented by the following interplanar spacings: and
  • the present invention further provides a method for preparing the crystal of above-mentioned N-butyl-2, 2'-imino-bis (8-quinolinamine) , the method comprises the following steps:
  • step (2) dissolving the precipitate obtained by step (1) in alkaline solution, extracting with esters solvent, and subsequently concentrating the extraction liquid to obtain the refined product of N-butyl-2, 2'-imino-bis (8-quinolinamine) ;
  • the preparation method according to the present invention uses alcohols solvent to re-crystallize the N-butyl-2, 2'-imino-bis (8-quinolinamine) , the inventors have found that a good crystal can be obtained by using alcohols solvent. It should be pointed out that, although the present invention provides a preparation method of the crystal, it does not preclude that the crystal according to the present invention can be obtained by other methods.
  • the re-crystallization may comprise the following steps: completely dissolving the obtained refined product of N-butyl-2, 2'-imino-bis (8-quinolinamine) in alcohols solvent, standing at low temperature, and subsequently volatilizing the solvent to obtain the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) .
  • the low temperature may be -5°C to 5°C.
  • the crude product of N-butyl-2, 2'-imino-bis (8-quinolinamine) may be obtained by catalytic hydrogenating the raw material of N-butyl-2, 2'-imino-bis (8-nitro-quinolin) .
  • the halogenated alkanes solvent may be any halogenated alkane as long as it can dissolve N-butyl-2, 2'-imino-bis (8-quinolinamine) .
  • the acid may be a common substance with acidity, as long as it can salify N-butyl-2, 2'-imino-bis (8-quinolinamine) .
  • the alkali may be a common substance with alkalinity, as long as it can dissociate N-butyl-2, 2'-imino-bis (8-nitro-quinolin) from the acid addition salt thereof.
  • the halogenated alkanes solvent may be selected from dichloromethane or trichloromethane.
  • the acid may be selected from hydrochloric acid.
  • the alkaline solution may be selected from sodium hydroxide solution, sodium bicarbonate solution or sodium carbonate solution.
  • the esters solvent may be ethyl acetate.
  • the alcohols solvent may be selected from methanol, ethanol, n-butyl alcohol or isopropyl alcohol.
  • the present invention further provides a composition containing the above-mentioned crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) .
  • the composition is a pharmaceutical material or a pharmaceutical preparation.
  • the pharmaceutical material refers to the raw material that can be used for producing pharmaceutical preparation, it also can be called bulk drug;
  • the pharmaceutical preparation refers to a product prepared according to certain dosage form requirement, satisfying with the provision of relevant laws and regulations and the requirements of relevant standard, and can be directly provided to a user.
  • the composition is a pharmaceutical preparation
  • the pharmaceutical preparation can be obtained according to the conventional method in the art by adding or not adding excipients based on the crystal according to the present invention, and subsequently preparing into certain physical form according to specific requirement.
  • the present invention further provides the use of the above-mentioned crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) or the above-mentioned composition in the preparation of metal ions chelator (the metal ion chelator refers to a substance which can be combined with metal ions to form a relatively stable coordination compound, it is also called metal chelator) .
  • the metal ion chelator refers to a substance which can be combined with metal ions to form a relatively stable coordination compound, it is also called metal chelator
  • the present invention further provides the use of the above-mentioned crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) or the above-mentioned composition in the preparation of the medicine for treating diseases, wherein the diseases are abnormal metal ion metabolic-related diseases, abnormal Tau protein-related diseases or abnormal beta-amyloid protein-related diseases.
  • the diseases are neurodegenerative diseases.
  • the neurodegenerative diseases are amyotrophic lateral sclerosis (ALS) , spinal muscular atrophy, ataxia telangiectasia, Creutzfeldt-Jakob disease, Huntington's disease, spinocerebellar ataxia, multiple sclerosis (MS) , Parkinson's disease, Alzheimer's disease (AD) or primary lateral sclerosis (PLS) .
  • ALS amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • AD Alzheimer's disease
  • PLS primary lateral sclerosis
  • the present invention provides a crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) , compared with the existing forms of existence of N-butyl-2, 2'-imino-bis (8-quinolinamine) , the crystal not only has all the common advantages of the crystalline substances, such as easy to subpackage, prepare the preparation and the like, but also surprisingly has excellent physical properties, especially the better water solubility and fat solubility.
  • Figure 1 shows a powder X-ray diffraction spectrum of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to Comparative Example 1 of the present invention.
  • Figure 2 shows a powder X-ray diffraction spectrum of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to Example 1 of the present invention.
  • Figure 3 shows a crystal morphology diagram of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to Example 1 of the present invention.
  • Figure 4 shows a crystalline spatial structure diagram of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to Example 1 of the present invention.
  • Figure 5 shows a single unit cell structure diagram of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to Example 1 of the present invention.
  • Figure 6 shows a spatial accumulation diagram of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to Example 1 of the present invention along b-axis.
  • Figure 7 shows a powder X-ray diffraction spectrum of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to Example 2 of the present invention.
  • the data in the present invention is impossible for the data in the present invention to be absolute due to the differences of the experimental conditions (including but not limited to the sample granularity, length-width ratio of the sample granule, instrument model, instrument precision, operating mode, operating personnel and the like) in the relevant analysis method and the unavoidability of the experimental errors (instrumental error, accidental error and the like) .
  • the inventors specify the error ranges of the data according to the common knowledge in the art and the nature of the compound N-butyl-2, 2'-imino-bis (8-quinolinamine) .
  • the error ranges cannot include all instances.
  • the data can be fluctuated in the general ranges in the art, all of which fall into the scope of the technical solutions of the present invention.
  • the powder X-ray diffraction method is performed by BRUKER D8 ADVANCE X-ray powder diffractometer; and the determination condition are as follows: CuK ⁇ radiation, tube voltage of 40 kV, 2 ⁇ scanning range of 5-60°, scanning speed of 17.7 s/step, and step length of 0.02°;
  • the single crystal X-ray diffraction method is performed by Bruker Smart APEXII diffractometer, the signal is acquired by Rigaku R-Axis Spider; the diffraction data is collected using Mok ⁇ radiation by ⁇ scanning mode and Lp correction; absorption correction is conducted by SADASB program; the structure is analyzed by direct method; all the non-hydrogen atoms are found by the difference Fourier method, partial hydrogen atoms are obtained by theoretical hydrogenation, partial hydrogen atoms are found from the difference Fourier diagram; and the structure is corrected by least square method;
  • the method for preparing the crude product of N-butyl-2, 2'-imino-bis (8-quinolinamine) comprises the following steps: according to the method for preparing “compound 23” in US8324196, dissolving N-butyl-2, 2'-imino-bis (8-nitroquinoline) (0.7g) in ethyl acetate, and adding palladium on carbon (0.15g, 10%) , and then bubbling hydrogen at a pressure of 1 bar, and subsequently stirring for 4 hours at room temperature. After the reaction is completed, palladium on carbon is filtrated out, and the filtrate is concentrated under reduced pressure to obtain the crude product of N-butyl-2, 2'-imino-bis (8-quinolinamine) .
  • the preparation method of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to the present invention comprised the following steps:
  • the crystal morphology of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) prepared by the above-mentioned step (3) is determined by powder X-ray diffraction method, the obtained spectrum is shown in Figure 2, and the main data of the powder X-ray diffraction spectrum is shown in Table 1.
  • the crystal morphology of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) prepared by the above-mentioned step (3) is determined by single crystal X-ray diffraction method, the parameters of single crystal unit cell are shown in Table 2, the crystal morphology is shown in Figure 3, the crystal spatial structure is shown in Figure 4, the structure of single unit cell is shown in Figure 5, and the accumulation mode of crystal along b-axis is shown in Figure 6.
  • Table 1 Main data of the powder X-ray diffraction spectrum
  • the preparation method of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to the present invention comprised the following steps:
  • the crystal morphology of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) prepared by the above-mentioned step (3) is determined by powder X-ray diffraction method, the obtained spectrum is shown in Figure 7, and the main data of the powder X-ray diffraction spectrum is shown in Table 3.
  • the crystal morphology of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) prepared by the above-mentioned step (3) is determined by single crystal X-ray diffraction method, and the parameters of single crystal unit cell are shown in Table 4.
  • Table 3 Main data of the powder X-ray diffraction spectrum
  • the preparation method of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to the present invention comprised the following steps:
  • the crystal morphology of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) prepared by the step (3) of the present Example is determined by powder X-ray diffraction method, the main data of the powder X-ray diffraction spectrum is shown in Table 5.
  • Table 5 Main data of the powder X-ray diffraction spectrum
  • the preparation method of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to the present invention comprised the following steps:
  • the crystal morphology of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) prepared by the step (3) of the present Example is determined by powder X-ray diffraction method, the main data of the powder X-ray diffraction spectrum is shown in Table 6.
  • the present Test Example investigates the solubility of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to the present invention, the specific investigation method was as follows:
  • Testing method adding 15 ml of the testing solvent into a centrifuge tube, and adding with excessive amounts of the testing sample until the undissolved testing sample appeared on the wall of the centrifuge tube. After sealing the centrifuge tubes by sealing film respectively, placing them in the constant water bath oscillators, and keeping the temperature at 37 ⁇ 1°C, after vibrating for 48 hour, centrifuging for 15 min at a speed of 3500 rpm, filtering the supernatant to determine the contents of N-butyl-2, 2'-imino-bis (8-quinolinamine) by ultraviolet-visible spectrophotometry, and subsequently calculating the equilibrium solubility (the unit of the equilibrium solubility is g/100ml) of each testing sample in the solvent, and the results are shown in Table 7.
  • the inventors of the present application surprisingly found that the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) had significant improvement in physical properties such as solubility and the like.
  • the solubility of the crystal provided by the present invention in the organic solvents such as n-butyl alcohol was about 2 times more than that of the existing forms, and the water solubility thereof was about 20 times more than that of the existing forms.
  • the pharmaceutical material or pharmaceutical preparation is a good metal ion chelator, and can be used for treating abnormal metal ion metabolic-related diseases, abnormal Tau protein-related diseases or abnormal beta-amyloid protein-related diseases.

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Abstract

The present invention provides the crystal of compound N-butyl-2,2'-imino-bis(8-quinolinamine), pharmaceutical composition and use thereof. The crystal compound N-butyl-2,2'-imino-bis(8-quinolinamine) according to the present invention has an excellent property of the preparation of drugs, and can be used for treating abnormal metal ion metabolic-related diseases, as well as the diseases associated with abnormal Tau protein metabolism and abnormal beta-amyloid protein, for example, the neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, ataxia telangiectasia, Creutzfeldt-Jakob disease, Huntington's disease, spinocerebellar ataxia, multiple sclerosis (MS), Parkinson's disease, Alzheimer's disease (AD), primary lateral sclerosis (PLS) and the like.

Description

CRYSTAL OF BIS (8-QUINOLINAMINE) DERIVATIVES Technical Field
The present invention relates to a crystal of bis (8-quinolinamine) derivatives, a composition and use thereof, particularly relates to a crystal of the compound of N-butyl-2, 2’-imino-bis (8-quinolinamine) , a composition and use thereof.
Background Art
N-butyl-2, 2’-imino-bis (8-quinolinamine) (compound A) is a multiple quinolines compound. US8324196 discloses that bis (8-substituted quinoline) derivatives including compound A are metal ion chelators, which can effectively reduce the accumulation of metal ions in the body.
The accumulation of the metal ions such as Na+, K+, Ca2+, Cu2+, Zn2+, Fe3+, Al3+ and the like can damage the relevant neuron cells of brain or spinal cord, and bring about a series of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) , spinal muscular atrophy, ataxia telangiectasia, Creutzfeldt-Jakob disease, Huntington's disease, spinocerebellar ataxia, multiple sclerosis (MS) , Parkinson's disease, Alzheimer's disease (AD) , primary lateral sclerosis (PLS) and the like. For example, metal ions with a high concentration can promote the accumulation of beta-amyloid protein, and induce the Tau protein to form a neurofibrillary tangle (NFT) ； while the two pathological changes of Alzheimer's disease (AD) are just the accumulation of beta-amyloid proteins outside the brain nervous cell and the neurofibrillary tangles formed by the hyperphosphorylation of Tau protein inside the nervous cell ( “Chinese Journal of Difficult and Complicated Cases” , 2015, 14 (3) , p319-322) .
In view of the potential medical application of compound A, it is necessary to conduct a further study on compound A.
US8324196 discloses a preparation method of compound A, comprising: catalytic hydrogenating the corresponding nitroquinoline derivatives to obtain crude product, and then dissolving the crude product in dichloromethane, and adding n-hexane to precipitate, thereby a brown powder is obtained.
The prior literature discloses a coordination compound formed of compound A and metallic copper ion, and the crystal structure of the coordination compound. The spatial structure shows that copper ions bond to four nitrogen atoms in the two  aminoquinolines of compound A, forming a stable crystal structure, and there are eight molecules of coordination compounds in one unit cell (see “European Journal of Inorganic Chemistry” , 2008, 36, p5622-5631) .
The change of the molecule microcosmic spatial structure may affect the property of the compound itself. Many studies on the coordination compound formed by the complexation of compound A and metal copper ion have been carried out in the prior art, however, there is no study on the crystallography of the compound A itself.
Summary of the Invention
The purpose of the present invention is to provide a crystal of N-butyl-2, 2’-imino-bis (8-quinolinamine) , preparation method and use thereof.
Meanwhile, the present invention further provides a composition containing the above-mentioned crystal of N-butyl-2, 2’-imino-bis (8-quinolinamine) and use thereof.
In order to achieve the above purposes, in the first aspect, the technical solution of the present application is as follows: a crystal of N-butyl-2, 2’-imino-bis (8-quinolinamine) , the structure of the N-butyl-2, 2’-imino-bis (8-quinolinamine) is represented by the following formula (I) ,
Figure PCTCN2016103606-appb-000001
The above-mentioned N-butyl-2, 2’-imino-bis (8-quinolinamine) is a known compound. However, when making improvement on the preparation method of the compound, the inventors surprisingly found that the product exists in a new form –crystal, i.e., N-butyl-2, 2’-imino-bis (8-quinolinamine) in the form of crystal (or called the crystal of N-butyl-2, 2’-imino-bis (8-quinolinamine) ) . The crystal refers to a substance formed by the regularly periodic repeated arrangement of the atoms, molecules and/or ions of compound in the space. The crystal is an orderly arrangement of the molecules of the substance； it has a significant difference in microstructure compared with the disordered arrangement such as amorphous arrangement.
The crystal can be characterized by powder X-ray diffraction analysis method. In such an analysis method, θ angle is also called grazing angle, it is an angle between  the incident ray and the crystal plane of the crystal. The X-ray at a specific grazing angle may be diffracted between certain crystal planes of the crystal when passing through the crystal, and it presents characteristic peaks (of which the intensity is greater than the noise) in the obtained spectrum. Thus, in the powder X-ray diffraction spectrum, the 2θ (diffraction angle) angle or the interplanar spacing (the distance between the crystal planes of the crystal substance) of the characteristic peaks can characteristically characterize the spatial structure of the crystal, and it can be distinguished from the existing forms of existence. The crystal of N-butyl-2, 2’-imino-bis (8-quinolinamine) can be characterized by powder X-ray diffraction analysis.
The result of powder X-ray diffraction analysis shows that, the crystal of N-butyl-2, 2’-imino-bis (8-quinolinamine) may comprise one or more characteristic peaks represented by the following 2θ angles in the powder X-ray diffraction spectrum: 6.70°±0.2°, 12.35°±0.2°, 13.75°±0.2°, 15.81°±0.2° and 19.72°±0.2°.
The result of powder X-ray diffraction analysis also shows that, the crystal of N-butyl-2, 2’-imino-bis (8-quinolinamine) according to the present invention may comprise one or more characteristic peaks represented by the following interplanar spacings in the powder X-ray diffraction spectrum: 
Figure PCTCN2016103606-appb-000002
Figure PCTCN2016103606-appb-000003
and
Figure PCTCN2016103606-appb-000004
It should be pointed out that, in the powder X-ray diffraction analysis spectrum, the peaks with low 2θ angle, high interplanar spacing, clear and integral shape and high strength tend to better reflect the characteristics of the crystal. Furthermore, for the issues such as preferred orientation of the samples and the like, the parameters of the single characteristic peaks, such as peak height, peak area and the like, tend to not have characteristics, and cannot be used alone to characterize the crystal.
As a preferred embodiment of the crystal of N-butyl-2, 2’-imino-bis (8-quinolinamine) according to the present invention, the powder X-ray diffraction spectrum of the crystal can further comprise one or more characteristic peaks represented by the following 2θ angles: 11.02°±0.2°, 17.02°±0.2°, 17.60°±0.2°, 19.00°±0.2°, 21.15°±0.2° and 22.12°±0.2°； correspondingly, the powder X-ray diffraction spectrum of the crystal can further comprise one or more characteristic peaks represented by the following interplanar spacings: 
Figure PCTCN2016103606-appb-000005
Figure PCTCN2016103606-appb-000006
and
Figure PCTCN2016103606-appb-000007
In a more  preferable embodiment, the powder X-ray diffraction spectrum of the crystal can further comprise one or more characteristic peaks represented by the following 2θangles: 22.79°±0.2°, 24.91°±0.2° and 27.12°±0.2°； correspondingly, the powder X-ray diffraction spectrum of the crystal can further comprise one or more characteristic peaks represented by the following interplanar spacings: 
Figure PCTCN2016103606-appb-000008
and
Figure PCTCN2016103606-appb-000009
As a preferred embodiment of the crystal of the N-butyl-2, 2’-imino-bis (8-quinolinamine) according to the present invention, the crystal belongs to monoclinic system, the space group is P21/c, its specific unit cell parameters are as follows: 
Figure PCTCN2016103606-appb-000010
α＝90.00°； 
Figure PCTCN2016103606-appb-000011
β＝98.5±1°； and 
Figure PCTCN2016103606-appb-000012
γ＝90.00°； unit cell volume is
Figure PCTCN2016103606-appb-000013
the number of molecules in unit cell is Z＝4. These unit cell parameters can be obtained through single crystal X-ray diffraction analysis.
In the second aspect, the present invention further provides a method for preparing the crystal of above-mentioned N-butyl-2, 2'-imino-bis (8-quinolinamine) , the method comprises the following steps:
(1) dissolving the crude N-butyl-2, 2'-imino-bis (8-quinolinamine) in halogenated alkanes solvent, and then adding acid to collect the precipitate；
(2) dissolving the precipitate obtained by step (1) in alkaline solution, extracting with esters solvent, and subsequently concentrating the extraction liquid to obtain the refined product of N-butyl-2, 2'-imino-bis (8-quinolinamine) ；
(3) re-crystallizing the refined product of N-butyl-2, 2'-imino-bis (8-quinolinamine) obtained by step (2) with alcohols solvent to obtain the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) .
The preparation method according to the present invention uses alcohols solvent to re-crystallize the N-butyl-2, 2'-imino-bis (8-quinolinamine) , the inventors have found that a good crystal can be obtained by using alcohols solvent. It should be pointed out that, although the present invention provides a preparation method of the crystal, it does not preclude that the crystal according to the present invention can be obtained by other methods.
In a preferred embodiment, the re-crystallization may comprise the following steps: completely dissolving the obtained refined product of N-butyl-2, 2'-imino-bis (8-quinolinamine) in alcohols solvent, standing at low  temperature, and subsequently volatilizing the solvent to obtain the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) . In a preferred embodiment, the low temperature may be -5℃ to 5℃.
In a preferred embodiment, the crude product of N-butyl-2, 2'-imino-bis (8-quinolinamine) may be obtained by catalytic hydrogenating the raw material of N-butyl-2, 2'-imino-bis (8-nitro-quinolin) .
The halogenated alkanes solvent may be any halogenated alkane as long as it can dissolve N-butyl-2, 2'-imino-bis (8-quinolinamine) . The acid may be a common substance with acidity, as long as it can salify N-butyl-2, 2'-imino-bis (8-quinolinamine) . The alkali may be a common substance with alkalinity, as long as it can dissociate N-butyl-2, 2'-imino-bis (8-nitro-quinolin) from the acid addition salt thereof.
As a preferred embodiment of the method for preparing the crystal of the N-butyl-2, 2'-imino-bis (8-quinolinamine) according to the present invention, the halogenated alkanes solvent may be selected from dichloromethane or trichloromethane. The acid may be selected from hydrochloric acid. The alkaline solution may be selected from sodium hydroxide solution, sodium bicarbonate solution or sodium carbonate solution. The esters solvent may be ethyl acetate. The alcohols solvent may be selected from methanol, ethanol, n-butyl alcohol or isopropyl alcohol.
In the third aspect, the present invention further provides a composition containing the above-mentioned crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) . Preferably, the composition is a pharmaceutical material or a pharmaceutical preparation. Wherein, the pharmaceutical material refers to the raw material that can be used for producing pharmaceutical preparation, it also can be called bulk drug； the pharmaceutical preparation refers to a product prepared according to certain dosage form requirement, satisfying with the provision of relevant laws and regulations and the requirements of relevant standard, and can be directly provided to a user. When the composition is a pharmaceutical preparation, the pharmaceutical preparation can be obtained according to the conventional method in the art by adding or not adding excipients based on the crystal according to the present invention, and subsequently preparing into certain physical form according to specific requirement.
In the fourth aspect, the present invention further provides the use of the  above-mentioned crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) or the above-mentioned composition in the preparation of metal ions chelator (the metal ion chelator refers to a substance which can be combined with metal ions to form a relatively stable coordination compound, it is also called metal chelator) . Meanwhile, the present invention further provides the use of the above-mentioned crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) or the above-mentioned composition in the preparation of the medicine for treating diseases, wherein the diseases are abnormal metal ion metabolic-related diseases, abnormal Tau protein-related diseases or abnormal beta-amyloid protein-related diseases.
As a preferred embodiment of the use of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to the invention or the composition in the preparation of the medicine for treating diseases, the diseases are neurodegenerative diseases. Preferably, the neurodegenerative diseases are amyotrophic lateral sclerosis (ALS) , spinal muscular atrophy, ataxia telangiectasia, Creutzfeldt-Jakob disease, Huntington's disease, spinocerebellar ataxia, multiple sclerosis (MS) , Parkinson's disease, Alzheimer's disease (AD) or primary lateral sclerosis (PLS) .
The beneficial effects of the present invention are as follows: the present invention provides a crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) , compared with the existing forms of existence of N-butyl-2, 2'-imino-bis (8-quinolinamine) , the crystal not only has all the common advantages of the crystalline substances, such as easy to subpackage, prepare the preparation and the like, but also surprisingly has excellent physical properties, especially the better water solubility and fat solubility.
In view of the poor water solubility of the compound N-butyl-2, 2'-imino-bis (8-quinolinamine) per se, it is difficult to prepare medicines (preparation of drugs) through the existing forms of existence of the compound. Therefore, the improvements of the water solubility and fat solubility have extremely important significance in improving the property of preparation of drugs of N-butyl-2, 2'-imino-bis (8-quinolinamine) and achieving the pharmaceutical application thereof.
Description of the Drawings
Figure 1 shows a powder X-ray diffraction spectrum of  N-butyl-2, 2'-imino-bis (8-quinolinamine) according to Comparative Example 1 of the present invention.
Figure 2 shows a powder X-ray diffraction spectrum of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to Example 1 of the present invention.
Figure 3 shows a crystal morphology diagram of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to Example 1 of the present invention.
Figure 4 shows a crystalline spatial structure diagram of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to Example 1 of the present invention.
Figure 5 shows a single unit cell structure diagram of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to Example 1 of the present invention.
Figure 6 shows a spatial accumulation diagram of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to Example 1 of the present invention along b-axis.
Figure 7 shows a powder X-ray diffraction spectrum of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to Example 2 of the present invention.
Best Mode
Hereinafter, Comparative Examples, Examples and Test Examples are not intended to limit the technical solutions and the technical effects of the present invention.
In the present invention, it is impossible for the data in the present invention to be absolute due to the differences of the experimental conditions (including but not limited to the sample granularity, length-width ratio of the sample granule, instrument model, instrument precision, operating mode, operating personnel and the like) in the relevant analysis method and the unavoidability of the experimental errors (instrumental error, accidental error and the like) . In order to scientifically characterize the crystal according to the present invention, the inventors specify the error ranges of the data according to the common knowledge in the art and the nature  of the compound N-butyl-2, 2'-imino-bis (8-quinolinamine) . However, it should be understood that, the error ranges cannot include all instances. A person skilled in the art should understand that, the data can be fluctuated in the general ranges in the art, all of which fall into the scope of the technical solutions of the present invention.
In the following Comparative Example and Examples:
(1) the powder X-ray diffraction method is performed by BRUKER D8 ADVANCE X-ray powder diffractometer； and the determination condition are as follows: CuKα radiation, tube voltage of 40 kV, 2θ scanning range of 5-60°, scanning speed of 17.7 s/step, and step length of 0.02°；
(2) the single crystal X-ray diffraction method is performed by Bruker Smart APEXII diffractometer, the signal is acquired by Rigaku R-Axis Spider； the diffraction data is collected using Mokα radiation
Figure PCTCN2016103606-appb-000014
by ω scanning mode and Lp correction； absorption correction is conducted by SADASB program； the structure is analyzed by direct method； all the non-hydrogen atoms are found by the difference Fourier method, partial hydrogen atoms are obtained by theoretical hydrogenation, partial hydrogen atoms are found from the difference Fourier diagram； and the structure is corrected by least square method；
(3) the determination conditions of ultraviolet-visible spectrophotometry are that: a mixed solution of Tris-HCl buffer solution ( [Tris-HCl] ＝20mM， [NaCl] ＝150mM， pH＝7.4) and methyl alcohol with a ratio of 1: 1 is used as the solvent, 302 nm is used as the measuring wavelength； and
(4) the experiments or experimental results may have certain errors due to the restriction of the test method per se, while it does not exert an effect on the understanding and the implementation of the present invention for a person skilled in the art.
In the following comparative example and examples, the method for preparing the crude product of N-butyl-2, 2'-imino-bis (8-quinolinamine) comprises the following steps: according to the method for preparing “compound 23” in US8324196, dissolving N-butyl-2, 2'-imino-bis (8-nitroquinoline) (0.7g) in ethyl acetate, and adding palladium on carbon (0.15g, 10％) , and then bubbling hydrogen at a pressure of 1 bar, and subsequently stirring for 4 hours at room temperature. After the reaction is completed, palladium on carbon is filtrated out, and the filtrate is concentrated under reduced pressure to obtain the crude product of  N-butyl-2, 2'-imino-bis (8-quinolinamine) .
Comparative Example 1：
In order to compare with the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to the present invention, the crude product of N-butyl-2, 2'-imino-bis (8-quinolinamine) was refined in the present comparative example according to the method of “compound 23” in US8324196: i.e., adding a small amounts of dichloromethane into the crude product of N-butyl-2, 2'-imino-bis (8-quinolinamine) to dissolve it, and adding four times volume (based on the volume of dichloromethane) of n-hexane to precipitate the product, after filtration, concentrating the filtrate under reduced pressure to obtain N-butyl-2, 2'-imino-bis (8-quinolinamine) in a form of a brown powder. Its diffraction spectrum is determined by powder X-ray diffraction, and the result is shown in Figure 1.
Example 1
As an example of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to the present invention, the preparation method of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to the present invention comprised the following steps:
(1) adding dichloromethane into 8.0 g of the crude product of N-butyl-2, 2'-imino-bis (8-quinolinamine) to dissolve it, and adding 400 mL of HCl with a concentration of 1 mol/L into the solution to precipitate N-butyl-2, 2'-imino-bis (8-quinolinamine) ；
(2) after filtration, adding 100 mL of sodium bicarbonate aqueous solution with a weight percentage concentration of 5％into the obtained filter cake to dissolve it, extracting with ethyl acetate, and subsequently concentrating the extraction liquid to obtain the refined product； the product was identified as N-butyl-2, 2'-imino-bis (8-quinolinamine) via NMR analysis； and
(3) dissolving 200mg of the above-mentioned refined product of N-butyl-2, 2'-imino-bis (8-quinolinamine) in 30 mL of methanol； and placing the mixture under the environment of 0℃ to 5℃, and subsequently standing to volatilize the solvent slowly, to obtain a yellow crystalline substance, i.e. the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) .
The crystal morphology of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) prepared by the above-mentioned step (3) is determined by powder X-ray diffraction method, the obtained spectrum is shown in Figure 2, and the main data of the powder X-ray diffraction spectrum is shown in Table 1.
The crystal morphology of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) prepared by the above-mentioned step (3) is determined by single crystal X-ray diffraction method, the parameters of single crystal unit cell are shown in Table 2, the crystal morphology is shown in Figure 3, the crystal spatial structure is shown in Figure 4, the structure of single unit cell is shown in Figure 5, and the accumulation mode of crystal along b-axis is shown in Figure 6.
Table 1: Main data of the powder X-ray diffraction spectrum
Figure PCTCN2016103606-appb-000015
Table 2: The parameters of single crystal unit cell
Figure PCTCN2016103606-appb-000016
Figure PCTCN2016103606-appb-000017
Example 2
As an example of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to the present invention, the preparation method of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to the present invention comprised the following steps:
(1) adding trichloromethane into 10.0 g of the crude product of N-butyl-2, 2'-imino-bis (8-quinolinamine) to dissolve it, and adding 600 mL of HCl with a concentration of 1 mol/L into the solution to precipitate N-butyl-2, 2'-imino-bis (8-quinolinamine) ；
(2) after filtration, adding 400 mL of sodium carbonate aqueous solution with a weight percentage concentration of 5％into the obtained filter cake to dissolve it, extracting with ethyl acetate, and subsequently concentrating the extraction liquid to obtain the refined product； the product was identified as N-butyl-2, 2'-imino-bis (8-quinolinamine) via NMR； and
(3) dissolving 300mg of the above-mentioned refined product of N-butyl-2, 2'-imino-bis (8-quinolinamine) in 40 mL of ethanol by heating； the temperature is slowly cooled to -5℃ to 0℃, standing at this temperature, and subsequently separating out a yellow crystalline substance, i.e. the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) .
The crystal morphology of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) prepared by the above-mentioned step (3) is determined by powder X-ray diffraction method, the obtained spectrum is shown in Figure 7, and the main data of the powder X-ray diffraction spectrum is shown in Table 3.
The crystal morphology of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) prepared by the above-mentioned step (3) is determined by single crystal X-ray diffraction method, and the parameters of single crystal unit cell are shown in Table 4.
Table 3: Main data of the powder X-ray diffraction spectrum
Figure PCTCN2016103606-appb-000018
Figure PCTCN2016103606-appb-000019
Table 4: The parameters of single crystal unit cell
Figure PCTCN2016103606-appb-000020
Example 3
As an example of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to the present invention, the preparation method of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to the present invention comprised the following steps:
(1) adding dichloromethane into 12.0 g of the crude product of N-butyl-2, 2'-imino-bis (8-quinolinamine) to dissolve it, and adding HCl with a concentration of 1 mol/L into the solution until no precipitate being produced；
(2) after filtration, adding 300 mL of sodium hydroxide aqueous solution with a weight percentage concentration of 1％into the obtained filter cake to dissolve it,  extracting with ethyl acetate, and subsequently concentrating the extraction liquid to obtain the refined product； the product was identified as N-butyl-2, 2'-imino-bis (8-quinolinamine) via NMR； and
(3) dissolving 500mg of the above-mentioned refined product of N-butyl-2, 2'-imino-bis (8-quinolinamine) in 40 mL of methanol by heating； the temperature is slowly cooled to 0℃ to 5℃, standing at this temperature, and subsequently separating out a yellow crystalline substance, i.e. the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) .
The crystal morphology of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) prepared by the step (3) of the present Example is determined by powder X-ray diffraction method, the main data of the powder X-ray diffraction spectrum is shown in Table 5.
Table 5: Main data of the powder X-ray diffraction spectrum
Figure PCTCN2016103606-appb-000021
Example 4
As an example of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to the present invention, the preparation method of the crystal of  N-butyl-2, 2'-imino-bis (8-quinolinamine) according to the present invention comprised the following steps:
(1) adding trichloromethane into 9.00 g of the crude product of N-butyl-2, 2'-imino-bis (8-quinolinamine) to dissolve it, and adding HCl with a concentration of 1 mol/L into the solution until no precipitate being produced；
(2) after filtration, adding 450 mL of sodium bicarbonate aqueous solution with a weight percentage concentration of 5％into the obtained filter cake to dissolve it, extracting with ethyl acetate, and subsequently concentrating the extraction liquid to obtain the refined product； the product was identified as N-butyl-2, 2'-imino-bis (8-quinolinamine) via NMR； and
(3) dissolving 300mg of the above-mentioned refined product of N-butyl-2, 2'-imino-bis (8-quinolinamine) in 30 mL of isopropyl alcohol, and placing the mixture under the environment of 0℃ to 5℃, and subsequently standing to volatilize the solvent slowly to obtain a yellow crystalline substance, i.e. the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) .
The crystal morphology of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) prepared by the step (3) of the present Example is determined by powder X-ray diffraction method, the main data of the powder X-ray diffraction spectrum is shown in Table 6.
Table 6: Main data of the powder X-ray diffraction spectrum
Figure PCTCN2016103606-appb-000022
Figure PCTCN2016103606-appb-000023
Test Example
The present Test Example investigates the solubility of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to the present invention, the specific investigation method was as follows:
Testing samples: the brown powder of N-butyl-2, 2'-imino-bis (8-quinolinamine) obtained by Comparative Example 1； and the crystals of N-butyl-2, 2'-imino-bis (8-quinolinamine) obtained by Examples 1-4.
Testing solvents: distilled water and n-butyl alcohol, operating respectively.
Testing method: adding 15 ml of the testing solvent into a centrifuge tube, and adding with excessive amounts of the testing sample until the undissolved testing sample appeared on the wall of the centrifuge tube. After sealing the centrifuge tubes by sealing film respectively, placing them in the constant water bath oscillators, and keeping the temperature at 37±1℃, after vibrating for 48 hour, centrifuging for 15 min at a speed of 3500 rpm, filtering the supernatant to determine the contents of N-butyl-2, 2'-imino-bis (8-quinolinamine) by ultraviolet-visible spectrophotometry, and subsequently calculating the equilibrium solubility (the unit of the equilibrium solubility is g/100ml) of each testing sample in the solvent, and the results are shown in Table 7.
Table 7: Equilibrium solubility (g/100ml)
Figure PCTCN2016103606-appb-000024
Through the above solubility experiments, the inventors of the present application surprisingly found that the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) had significant improvement in physical properties such as solubility and the like. The solubility of the crystal provided by the  present invention in the organic solvents such as n-butyl alcohol was about 2 times more than that of the existing forms, and the water solubility thereof was about 20 times more than that of the existing forms.
In view of the excellent water solubility and fat solubility of the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) , the inventors further investigated its properties, and found that it had a better property of the preparation of drugs, and it is more suitable for being used as the pharmaceutical material or the active ingredient in the pharmaceutical preparation. The pharmaceutical material or pharmaceutical preparation is a good metal ion chelator, and can be used for treating abnormal metal ion metabolic-related diseases, abnormal Tau protein-related diseases or abnormal beta-amyloid protein-related diseases.
Additionally, it should be pointed out that, the Examples described above are only for purposes of illustrating the technical solutions of the present invention and not intended to limit the protection scope of the present invention. Although the present invention is described in detail with reference to the preferred examples, it should be understood that a person skilled in the art can make modifications or substitution to the technical solution of the present invention without departing from the spirit and scope of the same. Besides, the contents of the background, summary of the invention and best mode described above are not used as the evidences for determining the prior art of the present invention.

Claims (14)

  1. A crystal of the compound of N-butyl-2, 2'-imino-bis (8-quinolinamine) .
  2. The crystal of the compound of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to claim 1, wherein the powder X-ray diffraction spectrum of the crystal comprises the characteristic peaks represented by the following 2θ angles: 6.70°±0.2°, 12.35°±0.2°, 13.75°±0.2°, 15.81°±0.2° and/or 19.72°±0.2°.
  3. The crystal of the compound of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to claim 2, wherein the powder X-ray diffraction spectrum of the crystal further comprises the characteristic peaks represented by the following 2θ angles:11.02°±0.2°, 17.02°±0.2°, 17.60°±0.2°, 19.00°±0.2°, 21.15°±0.2° and/or 22.12°±0.2°.
  4. The crystal of the compound of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to claim 3, wherein the powder X-ray diffraction spectrum of the crystal further comprises the characteristic peaks represented by the following 2θ angles:22.79°±0.2°, 24.91°±0.2° and/or 27.12°±0.2°.
  5. The crystal of the compound of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to claim 1, wherein the powder X-ray diffraction spectrum of the crystal comprises the characteristic peaks represented by the following interplanar spacings:
    Figure PCTCN2016103606-appb-100001
    and/or
    Figure PCTCN2016103606-appb-100002
  6. The crystal of the compound of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to claim 5, wherein the powder X-ray diffraction spectrum of the crystal further comprises the characteristic peaks represented by the following interplanar spacings:
    Figure PCTCN2016103606-appb-100003
    and/or
    Figure PCTCN2016103606-appb-100004
  7. The crystal of the compound of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to claim 6, wherein the powder X-ray diffraction spectrum of the crystal further comprises the characteristic peaks represented by the following interplanar spacings:
    Figure PCTCN2016103606-appb-100005
    and/or
    Figure PCTCN2016103606-appb-100006
  8. The crystal of the compound of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to claim 1, wherein the unit cell parameters in single crystal of the crystal are:
    Figure PCTCN2016103606-appb-100007
    α＝90.00°；
    Figure PCTCN2016103606-appb-100008
    β＝98.5±1°；
    Figure PCTCN2016103606-appb-100009
    γ＝90.00°；unit cell volume
    Figure PCTCN2016103606-appb-100010
    the number of molecules in unit cell Z＝4.
  9. A method for preparing the crystal of the compound of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to any one of claims 1-8,  comprising the following steps:
    (1) dissolving the crude N-butyl-2, 2'-imino-bis (8-quinolinamine) in halogenated alkanes solvent, and then adding acid to collect the precipitate；
    (2) dissolving the precipitate obtained by step (1) in alkaline solution, extracting with esters solvent, and subsequently concentrating the extraction liquid to obtain the refined product of N-butyl-2, 2'-imino-bis (8-quinolinamine) ； and
    (3) re-crystallizing the refined product of N-butyl-2, 2'-imino-bis (8-quinolinamine) obtained by step (2) with alcohols solvent to obtain the crystal of N-butyl-2, 2'-imino-bis (8-quinolinamine) .
  10. The preparation method according to claim 9, wherein the halogenated alkanes solvent is dichloromethane or trichloromethane；
    and/or, the acid is hydrochloric acid；
    and/or, the alkaline solution is sodium hydroxide solution, sodium bicarbonate solution or sodium carbonate solution；
    and/or, the esters solvent is ethyl acetate；
    and/or, the alcohols solvent is methanol, ethanol, n-butyl alcohol or isopropyl alcohol.
  11. A composition containing the crystal of the compound of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to any one of claims 1-8.
  12. The composition according to claim 11, wherein the composition is pharmaceutical material or pharmaceutical preparation.
  13. Use of the crystal of the compound of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to any one of claims 1-8 or the composition according to claim 11 or 12 in the preparation of metal ions chelator.
  14. Use of the crystal of the compound of N-butyl-2, 2'-imino-bis (8-quinolinamine) according to any one of claims 1-8 or the composition according to claim 11 or 12 in the preparation of drugs for treating diseases, wherein the diseases are abnormal metal ion metabolic-related diseases, abnormal Tau protein-related diseases or abnormal beta-amyloid protein-related diseases； preferably, the diseases are neurodegenerative diseases； more preferably, the neurodegenerative diseases are amyotrophic lateral sclerosis (ALS) , spinal muscular atrophy, ataxia telangiectasia, Creutzfeldt-Jakob disease, Huntington's disease, spinocerebellar ataxia, multiple sclerosis (MS) , Parkinson's disease, Alzheimer's  disease (AD) or primary lateral sclerosis (PLS) .
PCT/CN2016/103606 2016-10-27 2016-10-27 Crystal of bis(8-quinolinamine) derivatives WO2018076245A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8324196B2 (en) * 2005-08-04 2012-12-04 Palumed S.A. Polyquinoline derivatives and the therapeutic use thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8324196B2 (en) * 2005-08-04 2012-12-04 Palumed S.A. Polyquinoline derivatives and the therapeutic use thereof

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