CN104945453B - The polymorph of pyrazole derivatives - Google Patents
The polymorph of pyrazole derivatives Download PDFInfo
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- CN104945453B CN104945453B CN201410123690.XA CN201410123690A CN104945453B CN 104945453 B CN104945453 B CN 104945453B CN 201410123690 A CN201410123690 A CN 201410123690A CN 104945453 B CN104945453 B CN 104945453B
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- APWNJAHVEIVNTL-JHRCHIPJSA-N CCCN(CC1)C[C@H]1c1n[n](C)c2nc(OC(C(C(C3O)O)O)OC3C(O)=O)c(CCCC3)c3c12 Chemical compound CCCN(CC1)C[C@H]1c1n[n](C)c2nc(OC(C(C(C3O)O)O)OC3C(O)=O)c(CCCC3)c3c12 APWNJAHVEIVNTL-JHRCHIPJSA-N 0.000 description 1
Abstract
The polymorph of pyrazole derivatives of the present invention discloses a kind of formula（I）Compound crystal form,Or formula（I）Compound crystal form solvate or formula（I）Compound crystal form salt or formula（I）Compound crystal form salt solvate.The compound can be used for preparing drug of the treatment by the PARP diseases mediated.
Description
Technical field
The invention belongs to field of medicine preparing technology, and in particular to one kind 3,4,5- trihydroxies -6-（3- methyl-（1- third
Base-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene -2H- pyrans -
The polymorph of 2- formic acid.
Background technology
Poly adenosine diphosphate-ribose polymerase-1 (poly (ADP-ribose) polymerase, PARP), also referred to as poly- adenosine
Diphosphonic acid ribose synzyme（PARS）Or poly- adenosine diphosphate transferase（PADPRT）, it is a pass being present in eukaryocyte
One of key nucleus enzyme family.Up to the present, this cell ribozyme large family of the PARP having been acknowledged has 18 members, wherein
The most abundant member PARP-1 of content plays the polymerization of more than 90% diphosphonic acid ribose.
In another member's PARP-2 structure and PARP-1 is closest, and the two all contains 3 regions：One be contain there are two
The DNA of " zinc finger " structure is combined and nucleic acid localization region, the damage that this region passes through " zinc finger " structure recognition DNA；Secondly
Center includes 15 highly conserved glutaminic acid residues from modified regions, it is considered to be itself poly- adenosine diphosphate is ribosylating
Target position；Third is the C-terminal region containing NAD binding sites and the poly- adenosine diphosphate ribose catalytic site of synthesis.In the whole body of people
In cell, especially in immunocyte and reproduction cell, the content of PARP is quite abundant.Have in many physiology courses
The poly- ribosylating generations of ADP, multiple action includes chromatinic degradation, the duplication of DNA, the reparation of DNA, gene are expressed, carefully
The division and differentiation of born of the same parents and the apoptosis of cell.
PARP also adjusts the expression of various albumen, NO synzyme including transmitting inflammation etc. in transcriptional level.PARP conducts
The sensor of the single-stranded or double-stranded damage of DNA, plays a crucial role in DNA damage response.When the double-strand of DNA or single-stranded due to spoke
It penetrates, when oxidant and the effects that alkylating drug are broken, PARP activity can significantly increase.Once being activated, PARP is by NAD
It is cut into niacinamide and ADP ribose and the latter is aggregated to the nuclear receptor protein including histone, transcription factor and PARP in itself
On, form a hyperbranched adenosine diphosphate ribose high polymer similar to nucleic acid（PAR）.With this of height negative electrical charge
The formation of high polymer leads to the electrostatic pulse between DNA and combined protein, chromatin Structure relaxation.
PARP is conducive to chromatin recombination, DNA is repaired and the progress of transcriptional regulatory.Cause other such as XRCC1/
The intrusion of the DNA repair enzymes such as LIGIII is the committed step of DNA repair mechanisms.Poly adenosine diphosphate-ribose polymerase-1 is damaged in DNA
Effect played in wound has two opposite aspects：On the one hand, PARP is cell survival and is kept for one of chromosome stabilityX
Key factor；On the other hand, PARP excessive activations are the one of the major reasons for leading to cell death.Generate the main of this contradiction
Reason is environmental stimuli（Such as alkylating reagent, ray, oxidation）The difference of caused DNA damage degree.When cell by
During slight damage, PARP is activated, and repairs the position of damage；When cell is by stronger damage, PARP by excessive activation,
A large amount of NAD will be consumed, and then exhausts the ATP in cell, cell is made to be in energy deficient states, so as to cause the necrosis of cell
Or apoptosis.
Compound 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes-
3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene -2H- pyrans -2- formic acid, structure is such as：
WO2011147296 and PARP inhibitor medicaments are first disclosed as, for treating breast cancer, oophoroma, black
The tumor diseases such as plain knurl, prostate cancer, cancer of pancreas, glioma, colon cancer.To being used for the compound of bulk pharmaceutical chemicals and drug development
（I）Other solid forms there is demands.The present invention comes therefrom.
Invention content
Present invention aims at provide a kind of 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidines -3-
Base）- 6,7,8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The novel crystal forms of tetrahydrochysene -2H- pyrans -2- formic acid
Object, including solvate forms.These polymorphics are shown available for obtaining new pharmacological property and available for bulk pharmaceutical chemicals and drug
The new physics property of product development.
In order to solve the problems, such as it is of the prior art these, technical solution provided by the invention is：
A kind of formula（I）Compound crystal form,
Or formula（I）Compound crystal form solvate or formula（I）Compound crystal form
Salt or formula（I）Compound crystal form salt solvate.
Preferred formula（I）Compound crystal form solvate, with crystal form A, wherein the polymorph by
Powder X-ray RD spectral characterizations, the powder X-ray RD spectrum 7.412 ° of the 2 θ angles of diffraction, 9.451 °, 12.094 °, 12.990 °,
13.459°、14.185°、14.674°、14.999°、16.499°、17.131°、18.090°、19.393°、19.606°、
21.320°、21.961°、22.570°、23.238°、23.867°、24.117°、24.444°、25.822°、28.188°、
There is peak at 29.099 °, 30.145 °, 30.732 °, 32.883 °, 33.784 °, 35.299 ° and 38.492 °；The wherein 2 θ angles of diffraction
Error is +/- 0.2 °.
Preferred formula（I）Compound crystal form solvate, there is XRD spectrum as shown in figure 1 and table 1.
Preferred formula（I）Compound crystal form solvate, with crystal form B, wherein the polymorph by
Powder X-ray RD spectral characterizations, the powder X-ray RD spectrum 5.509 ° of the 2 θ angles of diffraction, 6.333 °, 8.367 °, 10.184 °,
12.785°、13.936°、14.568°、15.000°、16.670°、16.826°、17.186°、17.773°、18.630°、
There is peak at 19.391 °, 20.750 °, 22.350 °, 23.038 °, 23.745 °, 24.900 °, 25.393 °；The wherein 2 θ angles of diffraction
Error is +/- 0.2 °.
Preferred formula（I）Compound crystal form solvate, there is XRD spectrum as shown in Fig. 2 and table 2.
Preferred formula（I）Compound crystal form solvate, with crystal form C, wherein the polymorph by
Powder X-ray RD spectral characterizations, the powder X-ray RD spectrum 7.327 ° of the 2 θ angles of diffraction, 8.506 °, 9.365 °, 10.257 °,
11.211°、12.013°、12.889°、13.431°、13.976°、14.665°、15.088°、15.731°、16.389°、
16.962°、17.820°、18.679°、19.495°、21.232°、22.452°、23.153°、23.752°、24.984°、
There is peak at 25.741 °, 26.876 °, 28.071 °, 29.989 °；Wherein 2 θ diffraction angle errors are +/- 0.2 °.
Preferred formula（I）Compound crystal form solvate, there is XRD spectrum as shown in Fig. 3 and table 3.
Preferred formula（I）Compound crystal form solvate, with crystal form D, wherein the polymorph by
Powder X-ray RD spectral characterizations, the powder X-ray RD spectrum 8.862 ° of the 2 θ angles of diffraction, 10.488 °, 11.212 °, 11.421 °,
12.717°、13.968°、14.335°、15.025°、17.959°、19.063°、19.627°、21.239°、21.978°、
There is peak at 22.624 °, 23.437 °, 24.697 °, 26.667 °, 28.195 °, 31.235 °, 35.724 °；The wherein 2 θ angles of diffraction
Error is +/- 0.2 °.
Preferred formula（I）Compound crystal form solvate, there is XRD spectrum as shown in Fig. 4 and table 4.
Preferred formula（I）Compound crystal form solvate, with polymorphic E, wherein the polymorph
By powder X-ray RD spectral characterizations, the powder X-ray RD spectrum 7.211 ° of the 2 θ angles of diffraction, 8.949 °, 9.267 °, 10.633 °,
11.245°、11.505°、11.702°、12.799°、14.127°、15.269°、16.321°、18.187°、19.238°、
21.247°、22.200°、22.898°、23.255°、23.653°、23.959°、25.771°、26.828°、28.477°、
35.495 there is peak at °；Wherein 2 θ diffraction angle errors are +/- 0.2 °.
Preferred formula（I）Compound crystal form solvate, there is XRD spectrum as shown in Fig. 5 and table 5.
Preferred formula（I）Compound, with the wherein described polymorphs of polymorphic F by powder X-ray RD spectral characterizations, institute
State powder X-ray RD spectrum 7.268 ° of the 2 θ angles of diffraction, 10.158 °, 13.020 °, 13.496 °, 14.708 °, 15.975 °,
16.972°、17.994°、19.582°、20.414°、21.226°、22.168°、23.085°、24.112°、26.290°、
There is peak at 28.405 °, 30.936 °, 36.389 °；Wherein 2 θ diffraction angle errors are +/- 0.2 °.
Preferred formula（I）Compound, there is XRD spectrum as shown in Fig. 6 and table 6.
Preferred formula（I）Compound, with the wherein described polymorphs of polymorphic G by powder X-ray RD spectral characterizations, institute
State powder X-ray RD spectrum 7.306 ° of the 2 θ angles of diffraction, 9.087 °, 10.704 °, 11.358 °, 11.732 °, 13.130 °, 14.285 °,
15.338°、16.949°、18.217°、19.312°、19.871°、21.677°、22.282°、23.253°、23.937°、
There is peak at 24.995 °, 26.926 °, 28.691 °, 31.586 °, 35.946 °；Wherein 2 θ diffraction angle errors are +/- 0.2 °.
Preferred formula（I）Compound, there is XRD spectrum as shown in Fig. 7 and table 7.
Another object of the present invention is to provide a kind of pharmaceutical composition, described pharmaceutical composition includes the crystallization
Close object and pharmaceutically acceptable carrier or diluent.
It is a kind of for treating the method by the PARP diseases mediated another object of the present invention is to provide, including giving
Need the compound of the patient effective amounts of this treatment.
Preferably, the disease mediated by PARP is selected from breast cancer, oophoroma, melanoma, prostate cancer, pancreas
Cancer, glioma, colon cancer.
Another object of the present invention is to provide a kind of crystalline compounds preparation to be mediated by PARP for treating
Disease drug purposes.
Preferably, the disease is selected from breast cancer, oophoroma, melanoma, prostate cancer, cancer of pancreas, glioma, knot
Intestinal cancer.
Wherein described crystalline compounds for compound crystal form or compound crystal form solvate,
Or the solvate of the crystal form of the salt of the crystal form or compound of the salt of compound.
Another object of the present invention is to provide a kind of preparation method of the compound, the method includes by formula
（I）Compound water or the mixed solvents of water and other solvents the step of being crystallized.
Preferably, other solvents are selected from n-hexane, hexamethylene, ethyl cyclohexane, toluene, dimethylbenzene, chlorine in the method
Benzene, dichloromethane, chloroform, 1,2- dichloroethanes, methanol, ethyl alcohol, propyl alcohol, isopropanol, Ethyl formate, ethyl acetate, ether, benzene
Methyl ether, isopropyl ether, acetone, cyclohexanone, acetonitrile, tetrahydrofuran, DMF, dimethyl sulfoxide (DMSO) it is one or more kinds of arbitrary
Combination.
Preferably, the method specifically includes following steps：
（1）By compound 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- four
Hydrogen -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene -2H- pyrans -2- formic acid is added to water or water and other solvents
In the mixed solvent dissolves by heating；
（2）Precipitation solid is cooled to room temperature, white crystalline powder is obtained after natural air drying after filtering.
Preferably, the method further includes 3 will be prepared, 4,5- trihydroxy -6-（3- methyl-（1- propyl-
（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene -2H- pyrans -2-
The step of a kind of transformation of crystal of formic acid is into other crystal forms.
Preferably, 3,4,5- trihydroxy -6- in the method（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）-6,7,
8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The crystal form of tetrahydrochysene -2H- pyrans -2- formic acid is selected from 3,4,5- tri-
Hydroxyl -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -
5- oxygroups）The non-solvated crystal form and solvated Form of tetrahydrochysene -2H- pyrans -2- formic acid.
Compound 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes-
3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）A variety of crystal forms of tetrahydrochysene -2H- pyrans -2- formic acid, including the solvation with water
Object, solvate and tetrahydrochysene with the solvate of the solvate of the solvate of methanol and ethyl alcohol and ethyl alcohol and acetone
The solvate of furans, the solvate with N,N-dimethylformamide.
The solvate of crystal form and solvated Form are meaning of the same race in the present invention.That is 3,4,5- trihydroxies -6-（3-
Methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）- four
The water solvates of hydrogen -2H- pyrans -2- formic acid are 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidines -3-
Base）- 6,7,8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The aqueous solvent of tetrahydrochysene -2H- pyrans -2- formic acid
Crystal form.
Compound 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes-
3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The solvate of tetrahydrochysene -2H- pyrans -2- formic acid and water is melted at 180 DEG C
It decomposes simultaneously.
Compound 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes-
3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The preparation method of the solvate of tetrahydrochysene -2H- pyrans -2- formic acid and water is
By by compound 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes -3H-
Pyrazolo [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene -2H- pyrans -2- formic acid water or water and other mixed solvent crystallizations.
Used solvent is but is not limited to alkanes, such as：N-hexane, hexamethylene, ethyl cyclohexane；Aromatic hydrocarbon,
Such as：Toluene, dimethylbenzene, chlorobenzene；Alkyl halide, such as：Dichloromethane, chloroform, 1,2- dichloroethanes；Alcohols, such as：Methanol,
Ethyl alcohol, propyl alcohol, isopropanol；Esters, such as：Ethyl formate, ethyl acetate；Ethers, such as：Ether, methyl phenyl ethers anisole, isopropyl ether；Ketone
Class, such as：Acetone, cyclohexanone；Nitrile, such as：Acetonitrile；Furans, such as：Tetrahydrofuran；Amides, such as：DMF；Sulfoxide
Class, such as：Dimethyl sulfoxide (DMSO).
Can specifically it include the following steps：By by compound 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）-
Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene -2H- pyrans -2- formic acid
It is added to water or water and in the mixture of other solvents, heating for dissolving is subsequently cooled to room temperature and solid or suspension stirring, mistake is precipitated
Filter, filter cake is added in beaker, is added in after acetone stirs and wash, and filtering, filter cake is divided on culture dish, be placed at shady and cool ventilation from
White crystalline powder is obtained after so air-drying.
Compound 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes-
3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The solvate of tetrahydrochysene -2H- pyrans -2- formic acid and water can be in certain item
Other crystal forms are converted under part.
Compound 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes-
3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Other crystal forms of tetrahydrochysene -2H- pyrans -2- formic acid can be under certain condition
It is converted into the solvate with water.
Solvate with water, with the solvate of methanol, with the solvate of ethyl alcohol, with the solvate of ethyl alcohol, with
The solvate of the solvate of the solvate of acetone and tetrahydrofuran and N,N-dimethylformamide is under certain condition
It can mutually convert.
Solvate with water, with the solvate of methanol, with the solvate of ethyl alcohol, with the solvate of ethyl alcohol, with
The solvate of acetone, with the solvate of tetrahydrofuran, with the solvate of N,N-dimethylformamide, these compounds can
For prepare treatment PARP mediation disease drug purposes, the drug be used for PARP inhibitor, for treat breast cancer,
Oophoroma, melanoma, prostate cancer, cancer of pancreas, glioma, colon cancer.
Description of the drawings
The invention will be further described with reference to the accompanying drawings and embodiments：
Fig. 1 is 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes -3H-
Pyrazolo [3,4-c] isoquinolin -5- oxygroups）The X-ray powder diffraction spectrogram of the crystal form A of tetrahydrochysene -2H- pyrans -2- formic acid；
Fig. 2 is 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes -3H-
Pyrazolo [3,4-c] isoquinolin -5- oxygroups）The X-ray powder diffraction spectrogram of the crystal form B of tetrahydrochysene -2H- pyrans -2- formic acid；
Fig. 3 is 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes -3H-
Pyrazolo [3,4-c] isoquinolin -5- oxygroups）The X-ray powder diffraction spectrogram of the crystal form C of tetrahydrochysene -2H- pyrans -2- formic acid；
Fig. 4 is 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes -3H-
Pyrazolo [3,4-c] isoquinolin -5- oxygroups）The X-ray powder diffraction spectrogram of the crystal form D of tetrahydrochysene -2H- pyrans -2- formic acid；
Fig. 5 is 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes -3H-
Pyrazolo [3,4-c] isoquinolin -5- oxygroups）The X-ray powder diffraction spectrogram of the crystal form E of tetrahydrochysene -2H- pyrans -2- formic acid；
Fig. 6 is 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes -3H-
Pyrazolo [3,4-c] isoquinolin -5- oxygroups）The X-ray powder diffraction spectrogram of the crystal form F of tetrahydrochysene -2H- pyrans -2- formic acid；
Fig. 7 is 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes -3H-
Pyrazolo [3,4-c] isoquinolin -5- oxygroups）The X-ray powder diffraction spectrogram of the crystal form G of tetrahydrochysene -2H- pyrans -2- formic acid；
Fig. 8 is 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes -3H-
Pyrazolo [3,4-c] isoquinolin -5- oxygroups）The measurement result of the DSC and TGA of the crystal form A of tetrahydrochysene -2H- pyrans -2- formic acid.
Specific embodiment
Polymorphic and property
The present invention relates to 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- four
Hydrogen -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The crystal form of tetrahydrochysene -2H- pyrans -2- formic acid.3,4,5- trihydroxies-
6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygen
Base）Tetrahydrochysene -2H- pyrans -2- formic acid, also referred to as formula（I）Compound or chemical compounds I, it is initially described in
WO2011147296, the content of the patent are incorporated by reference the present invention.As described herein, chemical compounds I can be with
One or more polymorphic forms and existing crystal form, including solvate forms.These polymorphics (alternatively, exist
This field is referred to as polymorphic or crystal form) with regard to their X-ray powder diffraction figure, spectral quality, physicochemical property and medicine generation
It is different for kinetic property and their thermodynamic stability.
For some reason, it is expected different polymorphics, its solvate, its salt and its salt of acquisition crystalline compounds I
Solvate.For example, different polymorphics can include different impurity, that is, the impurity being contained in crystal form A in crystallization
It is not necessarily contained in crystal form B, C or D.Therefore, it polymorphous can prepare to improve final institute repeatedly using the difference of compound I
Obtain the purity of crystal form.In addition, different polymorphics can show different physical properties (such as fusing point, hygroscopicity, dissolubility,
Flow behavior or thermodynamic stability), therefore different polymorphics allows selection (to be used for example as medicine for given purpose or aspect
In object preparation process, in different form of medication (such as tablet, capsule, ointment, suspending agent or solvent) or manufacture have
Intermediate during the pharmaceutical dosage form of best pharmacokinetic property) most suitable form.
Therefore, in one aspect, the present invention provides a kind of crystal form of compound of formula (I) or the chemical combination of formula (I)
The knot of the salt of the crystal form of the compound of the solvate or formula (I) of the crystal form of object or the compound of formula (I)
The solvate of the salt of crystalline form.
The compound of formula (I) can have crystal form A.The one or more features signal from analysis measurement can be referred to determine
Adopted crystal form A；The analysis, which measures, to be included but is not limited to：X-ray powder diffraction figure, FT-IR spectrum or the differential of Fig. 1 is swept
Retouch calorimetry thermogram.
In an embodiment of the invention, the compound of formula (I) has crystal form A.Crystal form A is the compound of formula (I)
A kind of specific solvent compound, i.e., 3,4,5- trihydroxy -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）-6,7,8,9-
Tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The solvate of tetrahydrochysene -2H- pyrans -2- formic acid and water.The solvent
Compound can refer to the one or more features that (the including but not necessarily limited to X-ray powder diffraction figure of Fig. 1) is measured from analysis
Signal defines.Crystal form A can also be defined with reference to one or more of following characteristics signal characteristic signal：
Crystal form A represents with the 2 θ number of degrees, 7.412 ° of the 2 θ angles of diffraction, 9.451 °, 12.094 °, 12.990 °, 13.459 °,
14.185°、14.674°、14.999°、16.499°、17.131°、18.090°、19.393°、19.606°、21.320°、
21.961°、22.570°、23.238°、23.867°、24.117°、24.444°、25.822°、28.188°、29.099°、
There is peak at 30.145 °, 30.732 °, 32.883 °, 33.784 °, 35.299 ° and 38.492 °, wherein 2 θ diffraction angle errors are +/-
0.2°。
In another embodiment, crystal form A shows the X-ray powder diffraction figure substantially according to Fig. 1 and table 1.
The X-ray powder diffraction result of 1 crystal form A of table
| Peak number | The angle of diffraction（2θ） | D values | I/I0 |
| 1 | 7.412 | 11.9267 | 36.87 |
| 2 | 9.451 | 9.3579 | 100.00 |
| 3 | 12.094 | 7.3181 | 64.80 |
| 4 | 12.990 | 6.8161 | 17.24 |
| 5 | 13.459 | 6.5792 | 28.20 |
| 6 | 14.185 | 6.2440 | 6.34 |
| 7 | 14.674 | 6.0367 | 20.95 |
| 8 | 14.999 | 5.9066 | 8.28 |
| 9 | 16.499 | 5.3731 | 57.29 |
| 10 | 17.131 | 5.1762 | 14.42 |
| 11 | 18.090 | 4.9039 | 12.44 |
| 12 | 19.393 | 4.8237 | 10.39 |
| 13 | 19.606 | 4.5279 | 26.05 |
| 14 | 21.320 | 4.1676 | 52.51 |
| 15 | 21.961 | 4.0474 | 11.85 |
| 16 | 22.570 | 3.9396 | 13.61 |
| 17 | 23.238 | 3.8279 | 11.81 |
| 18 | 23.867 | 3.7284 | 65.17 |
| 19 | 24.117 | 3.6902 | 28.22 |
| 20 | 24.444 | 3.6416 | 20.40 |
| 21 | 25.822 | 3.4503 | 28.40 |
| 22 | 28.188 | 3.1659 | 15.69 |
| 23 | 29.099 | 3.0689 | 6.52 |
| 24 | 30.145 | 2.9647 | 9.17 |
| 25 | 30.732 | 2.9094 | 7.50 |
| 26 | 32.883 | 2.7238 | 7.06 |
| 27 | 33.784 | 2.6532 | 3.02 |
| 28 | 35.299 | 2.5427 | 6.45 |
| 29 | 38.492 | 2.3388 | 3.53 |
These characteristic signals be by the use of CuKa rays as characteristic X-ray powder diffraction in, 2 θ that collection of illustrative plates has spread out
Firing angle and D values, 2 θ diffraction angle errors are +/- 0.2 °.
It by heat analysis, is measured in the range of 30 to 300 DEG C, crystal form A can be further characterized.Fig. 8 show DSC and
The measurement result of TGA, collection of illustrative plates are swept in TAQ200 differentials acquired on calorimeter and TAQ500 thermogravimetric analyzers respectively.
Crystal form A shows the process for the water that decrystallizes between 34.9 DEG C to 100 DEG C, and 16.45% water loses, show there are five
The presence of the crystallization water（The theoretical value 15.5% of water content in solvate containing 5 crystallizations water（Weight ratio））.Dsc measurement knot
Fruit shows the fusion and decomposition between 180 DEG C to 300 DEG C.
In one embodiment, the compound of formula (I) has crystal form B.Crystal form B is the another kind of the compound of formula (I)
Specific solvent compound, i.e., 3,4,5- trihydroxy -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes-
3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The solvate of tetrahydrochysene -2H- pyrans -2- formic acid and methanol.The solvate
The one or more features signal from analysis measurement (X-ray powder diffraction figure including being not necessarily limited to Fig. 2) can be referred to come
Definition.Crystal form B can also be defined with reference to one or more of following characteristics signal characteristic signal：
In one embodiment, crystal form B 5.509 ° of the 2 θ angles of diffraction, 6.333 °, 8.367 °, 10.184 °, 12.785 °,
13.936°、14.568°、15.000°、16.670°、16.826°、17.186°、17.773°、18.630°、19.391°、
There is peak at 20.750 °, 22.350 °, 23.038 °, 23.745 °, 24.900 °, 25.393 °；Wherein 2 θ diffraction angle errors are +/-
0.2°.In another embodiment, crystal form B shows the X-ray powder diffraction figure substantially according to Fig. 2 and table 2.
The X-ray powder diffraction result of 2 crystal form B of table
| Peak number | The angle of diffraction（2θ） | D values | I/I0 |
| 1 | 5.509 | 16.0420 | 26.56 |
| 2 | 6.333 | 13.9562 | 22.17 |
| 3 | 8.367 | 10.5679 | 100.00 |
| 4 | 10.184 | 8.6861 | 95.06 |
| 5 | 12.785 | 6.9242 | 96.16 |
| 6 | 13.936 | 6.3549 | 57.79 |
| 7 | 14.568 | 6.0807 | 61.09 |
| 8 | 15.000 | 5.9064 | 25.11 |
| 9 | 16.670 | 5.6555 | 29.09 |
| 10 | 16.826 | 5.2693 | 30.39 |
| 11 | 17.186 | 5.1596 | 33.31 |
| 12 | 17.773 | 4.9908 | 59.42 |
| 13 | 18.630 | 4.7628 | 57.19 |
| 14 | 19.391 | 4.5778 | 54.53 |
| 15 | 20.750 | 4.2808 | 36.92 |
| 16 | 22.350 | 3.9778 | 36.02 |
| 17 | 23.038 | 3.8606 | 26.01 |
| 18 | 23.745 | 3.7472 | 33.83 |
| 19 | 24.900 | 3.5760 | 19.26 |
| 20 | 25.393 | 3.5076 | 11.38 |
These characteristic signals be by the use of CuKa rays as characteristic X-ray powder diffraction in, 2 θ that collection of illustrative plates has spread out
Firing angle and D values, 2 θ diffraction angle errors are +/- 0.2 °.
In one embodiment, the compound of formula (I) has crystal form C.Crystal form C is the another kind of the compound of formula (I)
Specific solvent compound, i.e., 3,4,5- trihydroxy -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes-
3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The solvate of tetrahydrochysene -2H- pyrans -2- formic acid and ethyl alcohol.The solvate
The one or more features signal that (the including but not necessarily limited to X-ray powder diffraction figure of Fig. 3) is measured from analysis can be referred to
To define.Crystal form C can also be defined with reference to one or more of following characteristics signal characteristic signal：
In one embodiment, crystal form C is shown to have and be represented with the 2 θ number of degrees, wherein the polymorph is by powder X-ray RD
Spectral characterization, the powder X-ray RD spectrum 7.327 ° of the 2 θ angles of diffraction, 8.506 °, 9.365 °, 10.257 °, 11.211 °,
12.013°、12.889°、13.431°、13.976°、14.665°、15.088°、15.731°、16.389°、16.962°、
17.820°、18.679°、19.495°、21.232°、22.452°、23.153°、23.752°、24.984°、25.741°、
There is peak at 26.876 °, 28.071 °, 29.989 °；Wherein 2 θ diffraction angle errors are +/- 0.2 °.In another embodiment,
Crystal form C shows the X-ray powder diffraction figure substantially according to Fig. 3 and table 3.
The X-ray powder diffraction result of 3 crystal form C of table
| Peak number | The angle of diffraction（2θ） | D values | I/I0 |
| 1 | 7.327 | 12.0646 | 30.98 |
| 2 | 8.506 | 10.3961 | 67.05 |
| 3 | 9.365 | 9.4442 | 98.62 |
| 4 | 10.257 | 8.6241 | 37.57 |
| 5 | 11.211 | 7.8929 | 20.31 |
| 6 | 12.013 | 7.3673 | 71.04 |
| 7 | 12.889 | 6.8685 | 79.31 |
| 8 | 13.431 | 6.5926 | 30.14 |
| 9 | 13.976 | 6.3368 | 51.40 |
| 10 | 14.665 | 6.0404 | 61.44 |
| 11 | 15.088 | 5.8720 | 22.94 |
| 12 | 15.731 | 5.6336 | 21.94 |
| 13 | 16.389 | 5.4089 | 55.27 |
| 14 | 16.962 | 5.2274 | 37.27 |
| 15 | 17.820 | 4.9775 | 58.57 |
| 16 | 18.679 | 4.7504 | 38.91 |
| 17 | 19.495 | 4.5535 | 62.57 |
| 18 | 21.232 | 4.1847 | 100.00 |
| 19 | 22.452 | 3.9600 | 52.20 |
| 20 | 23.153 | 3.8417 | 39.37 |
| 21 | 23.752 | 3.7462 | 89.45 |
| 22 | 24.984 | 3.5641 | 26.63 |
| 23 | 25.741 | 3.4610 | 38.18 |
| 24 | 26.876 | 3.3174 | 11.84 |
| 25 | 28.071 | 3.1788 | 21.82 |
| 26 | 29.989 | 2.9797 | 11.14 |
These characteristic signals be by the use of CuKa rays as characteristic X-ray powder diffraction in, 2 θ that collection of illustrative plates has spread out
Firing angle and D values, 2 θ diffraction angle errors are +/- 0.2 °.
In one embodiment, the compound of formula (I) has crystal form D.Crystal form D is the another kind of the compound of formula (I)
Specific solvent compound, i.e., 3,4,5- trihydroxy -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes-
3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The solvate of tetrahydrochysene -2H- pyrans -2- formic acid and ethyl alcohol.The solvate
The one or more features signal that (the including but not necessarily limited to X-ray powder diffraction figure of Fig. 4) is measured from analysis can be referred to
To define.Crystal form D can also be defined with reference to one or more of following characteristics signal characteristic signal：
In one embodiment, crystal form D is shown to have and be represented with the 2 θ number of degrees, wherein the polymorph is by powder X-ray RD
Spectral characterization, the powder X-ray RD spectrum 8.862 ° of the 2 θ angles of diffraction, 10.488 °, 11.212 °, 11.421 °, 12.717 °,
13.968°、14.335°、15.025°、17.959°、19.063°、19.627°、21.239°、21.978°、22.624°、
There is peak at 23.437 °, 24.697 °, 26.667 °, 28.195 °, 31.235 °, 35.724 °；Wherein 2 θ diffraction angle errors are +/-
0.2°.In another embodiment, crystal form D shows the X-ray powder diffraction figure substantially according to Fig. 4 and table 4.
The X-ray powder diffraction result of 4 crystal form D of table
| Peak number | The angle of diffraction（2θ） | D values | I/I0 |
| 1 | 8.862 | 9.9784 | 39.93 |
| 2 | 10.488 | 8.4353 | 25.27 |
| 3 | 11.212 | 7.8920 | 100.00 |
| 4 | 11.421 | 7.7482 | 96.86 |
| 5 | 12.717 | 6.9610 | 13.37 |
| 6 | 13.968 | 6.3403 | 87.92 |
| 7 | 14.335 | 6.1790 | 25.90 |
| 8 | 15.025 | 5.8966 | 36.85 |
| 9 | 17.959 | 4.9394 | 74.47 |
| 10 | 19.063 | 4.6556 | 65.50 |
| 11 | 19.627 | 4.5232 | 22.66 |
| 12 | 21.239 | 4.1834 | 81.61 |
| 13 | 21.978 | 4.0443 | 53.55 |
| 14 | 22.624 | 3.9303 | 29.49 |
| 15 | 23.437 | 3.7958 | 17.62 |
| 16 | 24.697 | 3.6050 | 13.77 |
| 17 | 26.667 | 3.3429 | 13.91 |
| 18 | 28.195 | 3.1651 | 10.54 |
| 19 | 31.235 | 2.8636 | 5.54 |
| 20 | 35.724 | 2.5135 | 3.63 |
These characteristic signals be by the use of CuKa rays as characteristic X-ray powder diffraction in, 2 θ that collection of illustrative plates has spread out
Firing angle and D values, 2 θ diffraction angle errors are +/- 0.2 °.
In one embodiment, the compound of formula (I) has crystal form E.Crystal form E is the another kind of the compound of formula (I)
Specific solvent compound, i.e., 3,4,5- trihydroxy -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes-
3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The solvate of tetrahydrochysene -2H- pyrans -2- formic acid and acetone.The solvate
The one or more features signal that (the including but not necessarily limited to X-ray powder diffraction figure of Fig. 5) is measured from analysis can be referred to
To define.Crystal form E can also be defined with reference to one or more of following characteristics signal characteristic signal：
In one embodiment, crystal form E is shown to have and be represented with the 2 θ number of degrees, wherein the polymorph is by powder X-ray RD
Spectral characterization, the powder X-ray RD spectrum 7.211 ° of the 2 θ angles of diffraction, 8.949 °, 9.267 °, 10.633 °, 11.245 °,
11.505°、11.702°、12.799°、14.127°、15.269°、16.321°、18.187°、19.238°、21.247°、
Have at 22.200 °, 22.898 °, 23.255 °, 23.653 °, 23.959 °, 25.771 °, 26.828 °, 28.477 °, 35.495 °
Peak；Wherein 2 θ diffraction angle errors are +/- 0.2 °.In another embodiment, crystal form E shows the X substantially according to Fig. 5 and table 5
Ray powder diffraction pattern.
The X-ray powder diffraction result of 5 crystal form E of table
| Peak number | The angle of diffraction（2θ） | D values | I/I0 |
| 1 | 7.211 | 12.2600 | 12.52 |
| 2 | 8.949 | 9.8816 | 25.24 |
| 3 | 9.267 | 9.5432 | 37.15 |
| 4 | 10.633 | 8.3207 | 13.28 |
| 5 | 11.245 | 7.8689 | 57.34 |
| 6 | 11.505 | 7.6916 | 52.82 |
| 7 | 11.702 | 7.5624 | 52.48 |
| 8 | 12.799 | 6.9169 | 17.05 |
| 9 | 14.127 | 6.2692 | 100.00 |
| 10 | 15.269 | 5.8030 | 26.29 |
| 11 | 16.321 | 5.4312 | 12.50 |
| 12 | 18.187 | 4.8778 | 62.44 |
| 13 | 19.238 | 4.6138 | 23.58 |
| 14 | 21.247 | 4.1819 | 54.86 |
| 15 | 22.200 | 4.0045 | 36.82 |
| 16 | 22.898 | 3.8840 | 33.11 |
| 17 | 23.255 | 3.8250 | 40.76 |
| 18 | 23.653 | 3.7616 | 39.84 |
| 19 | 23.959 | 3.7143 | 30.03 |
| 20 | 25.771 | 3.4571 | 10.60 |
| 21 | 26.828 | 3.3232 | 7.89 |
| 22 | 28.477 | 3.1345 | 8.68 |
| 23 | 35.495 | 2.5291 | 2.41 |
These characteristic signals be by the use of CuKa rays as characteristic X-ray powder diffraction in, 2 θ that collection of illustrative plates has spread out
Firing angle and D values, 2 θ diffraction angle errors are +/- 0.2 °.
In one embodiment, the compound of formula (I) has crystal form F.Crystal form F is that one kind of the compound of formula (I) is non-
Solvate.The non-solvent compound can be referred to be measured (the including but not necessarily limited to X-ray powder diffraction figure of Fig. 6) from analysis
One or more features signals define.It can also be defined with reference to one or more of following characteristics signal characteristic signal
Crystal form F：
In one embodiment, crystal form F is shown to have and be represented with the 2 θ number of degrees, wherein the polymorph is by powder X-ray RD
Spectral characterization, the powder X-ray RD spectrum 7.268 ° of the 2 θ angles of diffraction, 10.158 °, 13.020 °, 13.496 °, 14.708 °,
15.975°、16.972°、17.994°、19.582°、20.414°、21.226°、22.168°、23.085°、24.112°、
There is peak at 26.290 °, 28.405 °, 30.936 °, 36.389 °；Wherein 2 θ diffraction angle errors are +/- 0.2 °.In another reality
It applies in mode, crystal form F shows the X-ray powder diffraction figure substantially according to Fig. 6 and table 6.
The X-ray powder diffraction result of 6 crystal form F of table
| Peak number | The angle of diffraction（2θ） | D values | I/I0 |
| 1 | 7.268 | 12.1633 | 76.21 |
| 2 | 10.158 | 8.7082 | 19.00 |
| 3 | 13.020 | 6.7996 | 23.40 |
| 4 | 13.496 | 6.5610 | 26.56 |
| 5 | 14.708 | 6.0228 | 94.39 |
| 6 | 15.975 | 5.5482 | 14.71 |
| 7 | 16.972 | 5.2243 | 37.60 |
| 8 | 17.994 | 4.9298 | 100.00 |
| 9 | 19.582 | 4.5335 | 82.91 |
| 10 | 20.414 | 4.3505 | 36.99 |
| 11 | 21.226 | 4.1860 | 27.09 |
| 12 | 22.168 | 4.0102 | 54.13 |
| 13 | 23.085 | 3.8529 | 98.88 |
| 14 | 24.112 | 3.6911 | 16.64 |
| 15 | 26.290 | 3.3899 | 15.95 |
| 16 | 28.405 | 3.1423 | 7.14 |
| 17 | 30.936 | 2.8907 | 11.39 |
| 18 | 36.389 | 2.4691 | 15.61 |
These characteristic signals be by the use of CuKa rays as characteristic X-ray powder diffraction in, 2 θ that collection of illustrative plates has spread out
Firing angle and D values, 2 θ diffraction angle errors are +/- 0.2 °.
Also each provide crystal form F simultaneously（It is shown in Table 6）And crystal form G（It is shown in Table 7）X powder diffraction characteristic absorption peak（2θ）
As follows with D values, by the use of CuKa rays as characteristic X-ray, error is ± 0.2.
In one embodiment, the compound of formula (I) has crystal form G.Crystal form G is the another kind of the compound of formula (I)
Non-solvent compound.The non-solvent compound can refer to and measure (the including but not necessarily limited to X-ray powder diffraction of Fig. 7 from analysis
Figure) one or more features signals define.It can also come with reference to one or more of following characteristics signal characteristic signal
Define crystal form G：
In one embodiment, crystal form G is shown to have and be represented with the 2 θ number of degrees, wherein the polymorph is by powder X-ray RD
Spectral characterization, the powder X-ray RD spectrum 7.306 ° of the 2 θ angles of diffraction, 9.087 °, 10.704 °, 11.358 °, 11.732 °,
13.130°、14.285°、15.338°、16.949°、18.217°、19.312°、19.871°、21.677°、22.282°、
There is peak at 23.253 °, 23.937 °, 24.995 °, 26.926 °, 28.691 °, 31.586 °, 35.946 °；The wherein 2 θ angles of diffraction
Error is +/- 0.2 °.In another embodiment, crystal form G shows the X-ray powder diffraction figure substantially according to Fig. 7 and table 7.
The X-ray powder diffraction figure of 7 crystal form G of table
| Peak number | The angle of diffraction（2θ） | D values | I/I0 |
| 1 | 7.306 | 12.1006 | 13.50 |
| 2 | 9.087 | 9.7326 | 30.94 |
| 3 | 10.704 | 8.2654 | 18.98 |
| 4 | 11.358 | 7.7908 | 67.80 |
| 5 | 11.732 | 7.5434 | 54.10 |
| 6 | 13.130 | 6.7430 | 18.24 |
| 7 | 14.285 | 6.2005 | 73.09 |
| 8 | 15.338 | 5.7770 | 30.28 |
| 9 | 16.949 | 5.2315 | 10.89 |
| 10 | 18.217 | 4.8698 | 100.00 |
| 11 | 19.312 | 4.5962 | 47.90 |
| 12 | 19.871 | 4.4681 | 19.26 |
| 13 | 21.677 | 4.0998 | 64.35 |
| 14 | 22.282 | 3.9898 | 54.74 |
| 15 | 23.253 | 3.8254 | 58.58 |
| 16 | 23.937 | 3.7176 | 27.45 |
| 17 | 24.995 | 3.5626 | 17.30 |
| 18 | 26.926 | 3.3114 | 15.85 |
| 19 | 28.691 | 3.1115 | 8.70 |
| 20 | 31.586 | 3.8326 | 10.79 |
| 21 | 35.946 | 2.4984 | 7.64 |
These characteristic signals be by the use of CuKa rays as characteristic X-ray powder diffraction in, 2 θ that collection of illustrative plates has spread out
Firing angle and D values, 2 θ diffraction angle errors are +/- 0.2 °.
In one embodiment, crystal form A, B, C, D, E, F or G contains the total impurities less than 10 weight %.At another
In embodiment, crystal form A, B, C, D, E, F or G contain the total impurities less than 5 weight %.In another embodiment, crystal form
A, B, C, D, E, F or G contain the total impurities less than 2 weight %.
Terminology used in the present invention " solvate " refer to the compounds of this invention (including its pharmaceutically acceptable salt) with
The molecular complex of one or more solvent molecules.This solvent molecule be it is known to recipient in harmless pharmaceutical field often
Solvent molecule, such as water, ethyl alcohol etc..
Compound 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes-
3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The anhydrous crystal forms of tetrahydrochysene -2H- pyrans -2- formic acid are very unstable, easily
Occur to turn the phenomenon that brilliant, be unfavorable for the research of the related fields such as preparation.Therefore, to 3,4,5- trihydroxy -6- of compound（3- first
Base-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene-
A variety of crystal forms of 2H- pyrans -2- formic acid study particularly important and crucial.It searches out suitable for medicinal crystal form, to promoting this
The correlative study of the preparation of the compound that patent is related to and clinic is played the role of vital, while will further push
The development of PARP inhibitor antitumor drug correlative studys.
The present inventor in the course of the research, has found 3,4,5- trihydroxy -6- of compound（3- methyl-（1- propyl-（S）Pyrrole
Cough up alkane -3- bases）- 6,7,8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene -2H- pyrans -2- formic acid is deposited
In polymorphous phenomenon, it is found that 7 kinds of different crystal forms altogether（Crystal form A, B, C, D, E, F, G）, while also have surprisingly found that, wherein
Crystal form A has that purity is high, stability is good and the excellent characteristics such as solubility is relatively large, is suitble to preparation technical process and for a long time
Storage, and preparation process is simple, of low cost, is suitble to industrialized mass production.
One object of the present invention discloses 3,4,5- trihydroxy -6- of compound（3- methyl-（1- propyl-（S）Pyrroles
Alkane -3- bases）- 6,7,8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene -2H- pyrans -2- formic acid it is more
Kind crystal form.
Another object of the present invention discloses 3,4,5- trihydroxy -6- of compound（3- methyl-（1- propyl-（S）Pyrrole
Cough up alkane -3- bases）- 6,7,8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene -2H- pyrans -2- formic acid is not
Isomorphous preparation method.
A further object of the present invention discloses 3,4,5- trihydroxy -6- of compound（3- methyl-（1- propyl-（S）Pyrrole
Cough up alkane -3- bases）- 6,7,8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene -2H- pyrans -2- formic acid is fitted
In medicinal crystal form.
The present inventor is the study found that 3,4,5- trihydroxy -6- of compound（3- methyl-（1- propyl-（S）Pyrrolidines -3-
Base）- 6,7,8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene -2H- pyrans -2- formic acid has polymorphic
Phenomenon, it was found that five kinds of solvated Forms and two kinds are without hydrate crystal forms.
Compound 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysenes-
3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene -2H- pyrans -2- formic acid can form multi-solvents crystal form, including water
Solvate；The solvate of alcohol, such as：Methanol, ethyl alcohol；The solvate of ketone, such as：Acetone；The solvent of tetrahydrofuran
Compound；The solvate of N,N-dimethylformamide.
It should be understood that the solvate of the present invention may contain unbonded water, that is, it is not the water of the crystallization water.
It prepares
As described above, a kind of solid form (preferably crystal form) the invention further relates to compound for being used to prepare formula I,
The method of the solvate of its solvate, its salt and its salt.It can by rule of thumb and many methods suitable in practice are come
It determines to form the refined condition of specific polymorph, including crystallization condition as described in the present invention.The present invention also provides preparations
The method of crystal form A, comprising:
(1) by compound 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- four
Hydrogen -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene -2H- pyrans -2- formic acid be dispersed in water either water with it is a kind of or
The in the mixed solvent of various other solvents.
Other solvents include but is not limited to alkanes, such as：N-hexane, hexamethylene, ethyl cyclohexane；Aromatic hydrocarbon, example
Such as：Toluene, dimethylbenzene, chlorobenzene；Alkyl halide, such as：Dichloromethane, chloroform, 1,2- dichloroethanes；Alcohols, such as：Methanol, second
Alcohol, propyl alcohol, isopropanol；Esters, such as：Ethyl formate, ethyl acetate；Ethers, such as：Ether, methyl phenyl ethers anisole, isopropyl ether；Ketone,
Such as：Acetone, cyclohexanone；Nitrile, such as：Acetonitrile；Furans, such as：Tetrahydrofuran；Amides, such as：DMF；Sulfoxide type,
Such as：Dimethyl sulfoxide (DMSO).
（2）Under stiring, it after heating is completely dissolved, is cooled to room temperature, solid is precipitated；
（3）It filters out solid, acetone is added in solid stirs and wash after five minutes, filter out solid, solid dries, and obtains crystal form
A。
The preferred water of aforesaid operations method makees solvent, and crystallization prepares crystal form A, and concrete operations are as follows：
(1) by compound 3,4,5- trihydroxies -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- four
Hydrogen -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene -2H- pyrans -2- formic acid is dispersed in water；
（2）Under stiring, be warming up to 60-70 DEG C be completely dissolved after, after water-bath cooling to room temperature, be precipitated solid；
（3）It filters out solid, acetone is added in solid stirs and wash after five minutes, filter out solid, solid is divided in shady and cool ventilation
Place is dried, and obtains crystal form A.
Crystal form A can also be prepared by crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G conversions：
（1）At room temperature crystal form B is placed on to suspend in the mixed liquor of methanol and water and be stirred, V water：V methanol>1:3, preferably V water：
V methanol >=1:1, suspended matter is filtered out, obtains crystal form A；
（2）At room temperature crystal form C is placed on to suspend in the mixed liquor of ethyl alcohol and water and be stirred, V water：V ethyl alcohol>1:2, preferably V water：
V ethyl alcohol >=1:1, suspended matter is filtered out, obtains crystal form A；
（3）At room temperature crystal form D is placed on to suspend in the mixed liquor of ethyl alcohol and water and be stirred, V water：V ethyl alcohol>1:2, preferably V water：
V ethyl alcohol >=1:1, suspended matter is filtered out, obtains crystal form A；
（4）At room temperature crystal form E is placed on to suspend in the mixed liquor of acetone and water and be stirred, V water：V acetone>1:10, preferably V
Water：V acetone >=1:5, suspended matter is filtered out, obtains crystal form A.
（5）Crystal form F occurs to turn crystalline substance, forms a crystal form A in relative humidity >=90%.
（6）Crystal form G suspends stirring in the mixture of water or acetone and water, V water：V acetone >=1:5, filter out suspension
Object obtains crystal form A
Meanwhile crystal form A can also prepare crystal form B, crystal form C, crystal form D, crystal form E, crystal form F respectively by conversion.
（1）At room temperature crystal form A is placed on to suspend in the mixed liquor of methanol and water and be stirred, V water：V methanol<1:3, preferably V water：
V methanol≤1:5, suspended matter is filtered out, obtains crystal form B；
（2）At room temperature crystal form A is placed on to suspend in the mixed liquor of ethyl alcohol and water and be stirred, V water：V ethyl alcohol is 1:1 to 1:5 it
Between, preferred V water：V ethyl alcohol is 1:2 to 1:Between 3, suspended matter is filtered out, obtains crystal form C；
（3）At room temperature crystal form A is placed on to suspend in the mixed liquor of ethyl alcohol and water and be stirred, V water：V ethyl alcohol<5:1, preferably V water：
V ethyl alcohol≤1:10 filter out suspended matter, obtain crystal form D；
（4）At room temperature crystal form A is placed on to suspend in the mixed liquor of acetone and water and be stirred, V water：V acetone<1:10, it is preferably pure
Acetone filters out suspended matter, obtains crystal form E.
（5）Crystal form A is formed into crystal form F, while opposite behind temperature >=120 DEG C, the lower thermal dehydration of relative humidity≤7%
When the condition of humidity≤7% is cooled to 25 DEG C, crystal form F is obtained.
Meanwhile between above-mentioned crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G it is also that can mutually convert.
Such as：
（1）Crystal form C is added in the mixed liquor of ethyl alcohol and water at room temperature, V water：V ethyl alcohol<5:1, preferably V water：V ethyl alcohol
≤1:10 filter out suspended matter, obtain crystal form D；
（2）For crystal form E when being heated to 150 DEG C, dehydration obtains crystal form G；
（3）Crystal form G can be converted to crystal form F at 40 DEG C and RH≤20%.
In an embodiment of this method, warming temperature is in the range of 30-70 DEG C.
In the another embodiment of this method, warming temperature is in the range of 50-70 DEG C.
In the another embodiment of this method, warming temperature is in the range of 55-70 DEG C.In the another of this method
In a embodiment, warming temperature is in the range of 60-70 DEG C.
In the yet another embodiment of this method, mixture is sowed with one or more crystal of crystal form A（Make
For crystal seed seed）.
Terminology used in the present invention " crystal seed（seed）" can be one or more crystal of the compound of description formula (I).
Term " sowing（seed）" the one or more crystal to describe the compound of formula (I) import environment (including but not
Be limited to such as solvent, mixture, suspension or dispersion liquid) in thus lead to the row that the compound crystal of more formulas (I) is formed
For.
Other polymorphics can be prepared using the method described in embodiment 2 to embodiment 17.
The method for the treatment of
The present invention also provides a kind of a variety of because of PARP in the patient for needing this treatment for preventing, mitigating or treating
Clinical disease caused by active exception, such as the method for cancer, this method include giving a effective amount of formula (I) to the patient
Compound, particularly crystal form A, B, C, D, E, F or G.
Terminology used in the present invention " patient " refers to mammal, preferably people.
In one aspect, the present invention provide it is a kind of for treat by PARP diseases mediate method, this method including to
The patient of this treatment is needed to give the compound of a effective amount of formula (I), particularly crystal form A, B, C, D, E, F or G.
Can liver cancer, melanocyte be included but not limited to by the method or medicine composite for curing or this kind of disease of prevention of the present invention
Knurl, Hodgkin's disease, non-Hodgkin lymphoma, acute lymphatic leukaemia, chronic lymphocytic leukemia, Huppert's disease, into nerve
Cytoma, breast cancer, oophoroma, lung cancer, wilms' tumor, cervix cancer, carcinoma of testis, soft tissue sarcoma, the huge ball egg of primary
White mass formed by blood stasis, wing indulge in cancer, chronic myelocytic leukemia, primary brain cancer, chromoma, Small Cell Lung Cancer, gastric cancer, colon cancer,
Malignant pancreatic insulinoma, malignant carcinoid carcinomas, choriocarcinoma, gill fungus Sample Rou Ya Swollen, head or neck cancer, osteogenic sarcoma, cancer of pancreas,
Acute myeloblastic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi sarcoma, urogenital neoplasm disease, thyroid gland
Cancer, the cancer of the esophagus, malignant hypercalcemia, hyperplasia of cervix uteri disease, clear-cell carcinoma, carcinoma of endometrium, polycythemia vera, special hair
Property piastrenemia, adrenocortical carcinoma, cutaneum carcinoma and prostate cancer.Other diseases are also because of caused by PARP activity exceptions
Including but not limited to excessive cell death, including the central nervous system diseases such as apoplexy and neurodegenerative disease.
In the another embodiment of this method, disease is to be selected from：Breast cancer, oophoroma, melanoma, prostate
Cancer, cancer of pancreas, glioma, colon cancer.The compound of the present invention can be used for manufacturing drug, which inhibits for PARP
Agent, for treating breast cancer, oophoroma, melanoma, prostate cancer, cancer of pancreas, glioma, colon cancer.
In one aspect, the present invention provides a kind of method for treating disease listed above, and this method is included to need
The patient of this treatment is wanted to give the compound of a effective amount of formula (I), particularly crystal form A, B, C, D, E, F or G.In the opposing party
Face, the present invention provide a kind of method for treating disease caused by PARP activity exceptions, and this method includes this to needing
The patient for the treatment of gives the compound of a effective amount of formula (I) with crystal form A, B, C, D, E, F or G.The present invention also provides formulas
(I) compound, particularly crystal form A, B, C, D, E, F or G are used to prepare prevention, mitigation or treatment and are situated between by the activation of PARP
Lead the state of an illness, conditions or diseases drug purposes.
In one aspect, the compound of offer formula (I) of the present invention, particularly crystal form A, B, C, D, E, F or G are used to prepare
Treat the purposes by drug disease mediated PARP.In an embodiment of the purposes, disease is cancer, such as institute above
The disease listed.On the other hand, the compound of offer formula (I) of the present invention, particularly crystal form A, B, C, D, E, F or G are used for
Prepare the purposes for the drug for treating disease listed above.
Pharmaceutical composition
The compounds of this invention is suitable for the active constituent in pharmaceutical composition, the pharmaceutical composition can effectively treat with
The relevant diseases of PARP (such as cancer).Pharmaceutical composition in various embodiments has the formula (I) of pharmaceutical effective amount
It is compound (particularly crystal form A, B, C, D, E, F or G) and other pharmaceutically acceptable excipient, carrier, filler, dilute
Release agent etc.." pharmaceutical effective amount " or " pharmaceutically acceptable amount " refers to for treatment or prevention PARP relevant diseases, such as
The disease or the various forms of the state of an illness that prophylaxis of protein kinase relevant disease, particularly PARP associated diseases and/or the present invention describe
It is required or enough amounts for symptom and somatization.
Preparation of the term " pharmaceutical composition " including being suitable for administration to mammal (such as people).When the compounds of this invention is to make
When giving mammal (such as people) for drug, they can be (more excellent in the form of itself or to contain such as 0.1% to 99.9%
Selection of land 0.5 to 90%) active constituent gives together with the form of the pharmaceutical composition of pharmaceutically acceptable carrier.
Term " pharmaceutically acceptable carrier " is that the art is recognized, and including being suitable for chemical combination of the present invention
Object gives pharmaceutically acceptable material, composition or the supporting agent of mammal.Carrier includes participating in medicament from an organ
Or the liquid or solid filler, diluent, tax of another organ or body another part are taken or be transported in one part of body to
Shape agent, solvent or encapsulating material.Each carrier must be compatible with other ingredients of preparation and harmless aspect is " acceptable to patient
".Some examples that may be used as the material of pharmaceutically acceptable carrier include：Carbohydrate, such as lactose, dextrose and saccharose；It forms sediment
Powder class, such as cornstarch and potato starch；Cellulose and its derivative, for example, sodium carboxymethylcellulose, ethyl cellulose,
And cellulose acetate；Powdered gum tragacanth；Malt；Gelatin；Talcum；Excipient, such as cocoa butter and suppository wax class；Oils, such as flower
Oil generation, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil；Glycols, such as propylene glycol；Polyalcohols, it is such as sweet
Oil, D-sorbite, mannitol and polyethylene glycol；Esters, such as ethyl oleate and ethyl laurate；Agar；Buffer, such as hydroxide
Magnesium and aluminium hydroxide；Alginic acid；Apirogen water；Isotonic saline solution；Ringer's solution；Ethyl alcohol；Phosphate buffer solution；Pharmaceutical preparation
The middle other nontoxic compatible materials used.Wetting agent, emulsifier and lubricant (such as lauryl sodium sulfate and stearic acid
Magnesium) and colorant, releasing agent, coating agent, sweetener, corrigent and aromatic, preservative and antioxidant there may also be
In these compositions.
The preparation of the present invention is included suitable for oral medication, nose administration, local administration, oral administration, sublingual administration, rectum
The preparation of administration, vagina administration and/or parenteral.These preparations can easily use the form of unit dosage forms and can
To be prepared using any method well-known in pharmaceutical field.
On the other hand, the present invention provides a kind of comprising crystal form A and the drug of pharmaceutically acceptable carrier or diluent
Composition.In another embodiment, which includes crystal form B and pharmaceutically acceptable carrier or dilution
Agent.In another embodiment, which includes crystal form C and pharmaceutically acceptable carrier or diluent.
In yet another embodiment, which includes crystal form D and pharmaceutically acceptable carrier or diluent.
In one embodiment, the total weight of the compound based on composition Chinese style (I), pharmaceutical composition, which includes, to be less than
Crystal form A, B, C, D, E, F or G of 0.1 weight %.In another embodiment, compound based on composition Chinese style (I)
Total weight, pharmaceutical composition include crystal form A, B, C, D, E, F or G less than 1 weight %.In another embodiment, it is based on
The total weight of the compound of composition Chinese style (I), pharmaceutical composition include less than 10.0 weight % crystal form A, B, C, D, E, F or
Person G.In yet another embodiment, the total weight of the compound based on composition Chinese style (I), pharmaceutical composition, which includes, to be less than
Crystal form A, B, C, D, E, F or G of 50.0 weight %.In another embodiment, the compound based on composition Chinese style (I)
Total weight, pharmaceutical composition includes at least crystal form A, B, C, D, E, F or G of 50.0 weight %.In yet another embodiment
In, the total weight of the compound based on composition Chinese style (I), pharmaceutical composition include at least crystal form A, B of 75.0 weight %, C,
D, E, F or G.In another embodiment, the total weight of the compound based on composition Chinese style (I), pharmaceutical composition packet
Containing at least crystal form A, B, C, D, E, F or G of 99.0 weight %.In another embodiment, based on composition Chinese style (I)
The total weight of compound, pharmaceutical composition include at least crystal form A, B, C, D, E, F or G of 99.9 weight %.
Said program is described further below in conjunction with specific embodiment.It should be understood that these embodiments are for illustrating
The present invention and be not limited to limit the scope of the invention.The implementation condition used in embodiment can be done according to the condition of specific producer
Further adjustment, the implementation condition being not specified is usually the condition in routine experiment.3,4,5- tri- used in following embodiment
Hydroxyl -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -
5- oxygroups）Tetrahydrochysene -2H- pyrans -2- carboxylic acid compounds are synthesized according to the method that WO2011147296A1 is provided, and purity is
99.52%。
The preparation of 1 crystal form A of embodiment
Equipped with thermometer, stirring, condenser pipe 500mL three-necked flask in, add in 50g3,4,5- trihydroxy -6-（3-
Methyl-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）- four
Hydrogen -2H- pyrans -2- formic acid, while add in the stirring of 300mL pure water, 75 DEG C of heating water baths to complete dissolved clarification.
Water-bath cooling stirs 30min crystallizations, and a large amount of white solids are precipitated, and places refrigerator（5℃）4~5h is refrigerated, water pump is taken out
It filters to dripless.
Under the conditions of 25 DEG C, 250mL acetone agitator treating filter cake 30min, water pump filters, and filter cake elutes one with a small amount of acetone again
Secondary, water pump is filtered to dripless, is placed shady place natural air drying for 24 hours, is obtained 48.5g white crystalline powders, XRPD measurement results are shown
It is shown as crystal form A, purity 99.91%（HPLC normalization methods）.
2 crystal form B of embodiment is converted into crystal form A
Weigh the compound 3,4,5- trihydroxies -6- of 0.5g（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）-6,7,
8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene -2H- pyrans -2- aminic acid crystal B, are added to 50mL's
In beaker, 10mL is added in into beaker（VWater：VAbsolute methanol=3:1）Absolute methanol and pure water mixed liquor, at ambient temperature,
It suspends after stirring 0.5 hour, filters out solid suspension, off-white color crystalline solid powder is obtained after being dried with shady place, through X powder
Last diffractometry results are shown as crystal form A, purity 99.56%（HPLC normalization methods）.
3 crystal form C of embodiment is converted into crystal form A
Weigh the compound 3,4,5- trihydroxies -6- of 0.5g（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）-6,7,
8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene -2H- pyrans -2- aminic acid crystal C, are added to 50mL's
In beaker, 20mL is added in into beaker（VWater：VAbsolute ethyl alcohol=1:1）Absolute ethyl alcohol and pure water mixed liquor, at ambient temperature,
It suspends after stirring 0.5 hour, filters out solid suspension, off-white color crystalline solid powder is obtained after being dried with shady place, through X powder
Last diffractometry results are shown as crystal form A, purity 99.52%（HPLC normalization methods）.
4 crystal form D of embodiment is converted into crystal form A
Weigh the compound 3,4,5- trihydroxies -6- of 0.5g（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）-6,7,
8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene -2H- pyrans -2- aminic acid crystal D, are added to 50mL's
In beaker, 20mL is added in into beaker（VWater：VAbsolute ethyl alcohol=1:5）Absolute ethyl alcohol and pure water mixed liquor, at ambient temperature,
It suspends after stirring 0.5 hour, filters out solid suspension, off-white color crystalline solid powder is obtained after being dried with shady place, through X powder
Last diffractometry results are shown as crystal form A, purity 99.53%（HPLC normalization methods）.
5 crystal form E of embodiment is converted into crystal form A
Weigh the compound 3,4,5- trihydroxies -6- of 0.5g（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）-6,7,
8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene -2H- pyrans -2- aminic acid crystal E, are added to 50mL's
In beaker, 15mL is added in into beaker（VWater：VAcetone=1:5）Acetone and pure water mixed liquor, at ambient temperature, suspension is stirred
After mixing 0.5 hour, solid suspension is filtered out, off-white color crystalline solid powder is obtained after being dried with shady place, through X powder diffraction
Measurement result is shown as crystal form A, purity 99.59%（HPLC normalization methods）.
6 crystal form F of embodiment is converted into crystal form A
The measuring cup of clean dried is taken, is weighed as 45.6278g, adds in 3,4,5- trihydroxy -6- of minority specioz（3- first
Base-（1- propyl-（S）Pyrrolidin-3-yl）- 6,7,8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene-
It weighs after 2H- pyrans -2- aminic acid crystals F, measuring cup is put into constant-humidity constant-temperature case, temperature by sample and measuring cup gross weight 45.7803g
Degree control is weighed after being placed 5 days under the conditions of 25 DEG C, relative humidity 90 ± 5%, sample and measuring cup gross weight 45.8061, gain in weight
It is 16.92%, crystal form A, purity 99.56% is shown as through X powder diffraction measurement result（HPLC normalization methods）.
7 crystal form G of embodiment is converted into crystal form A
Weigh the compound 3,4,5- trihydroxies -6- of 0.5g（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）-6,7,
8,9- tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）Tetrahydrochysene -2H- pyrans -2- aminic acid crystal G, are added to 50mL's
In beaker, 15mL is added in into beaker（VWater：VAcetone=1:5）Acetone and pure water mixed liquor, at ambient temperature, suspension is stirred
After mixing 0.5 hour, solid suspension is filtered out, off-white color crystalline solid powder is obtained after being dried with shady place, through X powder diffraction
Measurement result is shown as crystal form A, purity 99.53%（HPLC normalization methods）.
8 crystal form A of embodiment is converted into crystal form B
At room temperature, by 2g3,4,5- trihydroxy -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）-6,7,8,9-
Tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The crystal form A compounds of tetrahydrochysene -2H- pyrans -2- formic acid, are added to
In the beaker of 100mL, while add in prepared V in advanceWater：VMethanol=1:10 mixed solution 12mL after stirring 30 minutes, is filtered
Go out suspended solid, be evacuated to dripless.
Filter cake shakeouts, and 1.76g white crystalline powders are obtained after being placed on shady and cool natural air drying, measures and ties through X powder diffraction
Fruit is shown as crystal form B, purity 99.63%（HPLC normalization methods）.
9 crystal form A of embodiment is converted into crystal form C
At room temperature, by 2g3,4,5- trihydroxy -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）-6,7,8,9-
Tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The crystal form A compounds of tetrahydrochysene -2H- pyrans -2- formic acid, are added to
In the beaker of 100mL, while add in prepared V in advanceWater：VEthyl alcohol=1:3 mixed solution 10mL after stirring 30 minutes, is filtered
Go out suspended solid, be evacuated to dripless.
Filter cake shakeouts, and 1.82g white crystalline powders are obtained after being placed on shady and cool natural air drying, measures and ties through X powder diffraction
Fruit is shown as crystal form C, purity 99.59%（HPLC normalization methods）.
10 crystal form A of embodiment is converted into crystal form D
At room temperature, by 2g3,4,5- trihydroxy -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）-6,7,8,9-
Tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The crystal form A compounds of tetrahydrochysene -2H- pyrans -2- formic acid, are added to
In the beaker of 100mL, while 20mL absolute ethyl alcohols are added in, after stirring 30 minutes, filter out suspended solid, be evacuated to dripless.Filter
Cake shakeouts, and 1.92g white crystalline powders are obtained after being placed on shady and cool natural air drying, is shown as brilliant through X powder diffraction measurement result
Type D, purity 99.63%（HPLC normalization methods）.
11 crystal form A of embodiment is converted into crystal form E
At room temperature, by 2g3,4,5- trihydroxy -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）-6,7,8,9-
Tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The crystal form A compounds of tetrahydrochysene -2H- pyrans -2- formic acid, are added to
In the beaker of 100mL, while 20mL anhydrous propanones are added in, after stirring 30 minutes, filter out suspended solid, be evacuated to dripless.Filter
Cake shakeouts, and 1.90g white crystalline powders are obtained after being placed on shady and cool natural air drying, is shown as brilliant through X powder diffraction measurement result
Type E, purity 99.65%（HPLC normalization methods）.
12 crystal form A of embodiment is converted into crystal form F
At room temperature, by 2g3,4,5- trihydroxy -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）-6,7,8,9-
Tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The crystal form A compounds of tetrahydrochysene -2H- pyrans -2- formic acid, divide and are training
It supports on ware, is placed in constant-humidity constant-temperature case, set temperature is 40 DEG C, and relative humidity 10% after 5 hours, takes sample detection.Outside
See still is white crystalline powder.Crystal form F, purity 99.58% are shown as through X powder diffraction measurement result（HPLC normalization methods）.
13 crystal form A of embodiment is converted into crystal form G
At room temperature, by 1g3,4,5- trihydroxy -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）-6,7,8,9-
Tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The crystal form A compounds of tetrahydrochysene -2H- pyrans -2- formic acid are flat to be tied
It on brilliant ware, is put into climatic chamber, temperature control is at 120 DEG C, and relative humidity was controlled after 7% or so, 3 hour, relatively wet
Degree is cooled to 25 DEG C under the conditions of being maintained at 7%, takes sample detection.Appearance is still white crystalline powder.It measures and ties through X powder diffraction
Fruit is shown as crystal form G, purity 99.58%（HPLC normalization methods）.
16 crystal form C of embodiment is converted into crystal form D
At room temperature, by 1g3,4,5- trihydroxy -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）-6,7,8,9-
Tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The crystal form C compounds of tetrahydrochysene -2H- pyrans -2- formic acid, are added to
In the beaker of 100mL, absolute ethyl alcohol 20mL suspends after stirring 30 minutes, filters out suspended solid, be evacuated to dripless.Filter cake is spread out
It is flat, 0.92g white crystalline powders are obtained after being placed on shady and cool natural air drying, XRPD measurement results are shown as crystal form D, purity
99.63%（HPLC normalization methods）.
17 crystal form E of embodiment is converted into crystal form G
At room temperature, by 1g3,4,5- trihydroxy -6-（3- methyl-（1- propyl-（S）Pyrrolidin-3-yl）-6,7,8,9-
Tetrahydrochysene -3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups）The crystal form E compounds of tetrahydrochysene -2H- pyrans -2- formic acid are flat to be tied
It on brilliant ware, is put into baking oven, temperature is controlled after 150 DEG C, 3 hours, takes sample detection.Appearance is still white crystalline powder.
XRPD measurement results are shown as crystal form G, purity 99.61%（HPLC normalization methods）.
The physical property of 18 crystal form of embodiment is investigated
After carrying out the correlations Quality Research such as further stability, solubility relatively to above-mentioned all crystal forms, this
Inventor has surprisingly found that, in the crystal form disclosed in the present invention, crystal form A has excellent characteristic：The crystal form solubility is good, this
It is of crucial importance to play drug curative effect, while also has purity height, stability good and simple for process, of low cost, in industry life
In production there is great superiority, be suitble to preparation technical process and long-term storage.
（1）Accelerated stability test
The accelerated stability test of crystal form A confirms above-mentioned discovery：
Stability test the result shows that, crystal form A is in accelerated stability test, appearance, X powder diffraction, heat analysis collection of illustrative plates
It does not change, illustrates stable crystal form, without trichite life is turned, still keep original crystal form；In addition, related substance, content are also equal
It does not change, illustrates that crystal form A chemical stabilities are preferable, be suitble to the manufacture of pharmaceutical preparation and long-term storage.
（2）The solubility experiment of crystal form A：
By 2010 editions two notes on the use of Chinese Pharmacopoeia（15）（2）Method as defined under has carried out crystal form A solubility reality
It tests, as a result：
| DMSO | H2O | |
| Crystal form A | 1/350 | 1/4.6 |
The dissolubility data of crystal form of the present invention, is represented with g/mL.
Solubility experiment the result shows that, the solubility of crystal form A is preferable, will improve bioavilability to a certain degree, greatly
Promotion curative effect of medication performance.
The foregoing examples are merely illustrative of the technical concept and features of the invention, its object is to allow the person skilled in the art to be
Present disclosure can be understood and implemented according to this, it is not intended to limit the scope of the present invention.It is all smart according to the present invention
The equivalent transformation or modification that refreshing essence is done, should be covered by the protection scope of the present invention.
Claims (5)
1. 5 hydrates of compound shown in a kind of formula (I),
5 hydrate powder X-ray RD spectral characterizations, the powder X-ray RD spectrum 7.412 ° of the 2 θ angles of diffraction, 9.451 °,
12.094°、12.990°、13.459°、14.185°、14.674°、14.999°、16.499°、17.131°、18.090°、
19.393°、19.606°、21.320°、21.961°、22.570°、23.238°、23.867°、24.117°、24.444°、
Have at 25.822 °, 28.188 °, 29.099 °, 30.145 °, 30.732 °, 32.883 °, 33.784 °, 35.299 ° and 38.492 °
There is peak；Wherein 2 θ diffraction angle errors are +/- 0.2 °.
2. 5 hydrate according to claim 1 has XRD spectrum as shown in figure 1 and table 1.
3. a kind of pharmaceutical composition includes 5 hydrate described in claim 1 and pharmaceutically acceptable carrier or dilution
Agent.
4. a kind of 5 hydrate described in claim 1 is in the purposes for preparing the drug for being used for treatment by the PARP diseases mediated.
5. a kind of preparation method of 5 hydrate described in claim 1, includes the following steps：
(1) by compound 3,4,5- trihydroxies -6- (3- methyl-(1- propyl-(S)-pyrrolidin-3-yl) -6,7,8,9- tetrahydrochysenes -
3H- pyrazolos [3,4-c] isoquinolin -5- oxygroups)-tetrahydrochysene -2H- pyrans -2- formic acid is added to the mixed of water or water and other solvents
In bonding solvent, dissolve by heating；
(2) precipitation solid is cooled to room temperature, white crystalline powder is obtained after natural air drying after filtering；
Wherein, other solvents are selected from：N-hexane, hexamethylene, ethyl cyclohexane, toluene, dimethylbenzene, chlorobenzene, dichloromethane, chlorine
Imitative, 1,2- dichloroethanes, methanol, ethyl alcohol, propyl alcohol, isopropanol, Ethyl formate, ethyl acetate, ether, methyl phenyl ethers anisole, isopropyl ether, third
Ketone, one or more kinds of arbitrary combinations of cyclohexanone, acetonitrile, tetrahydrofuran, DMF, dimethyl sulfoxide (DMSO).
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| CN114053271A (en) * | 2020-07-30 | 2022-02-18 | 江苏天士力帝益药业有限公司 | Pharmaceutical composition containing TSL-1502M and application thereof |
| CN114053415A (en) * | 2020-07-30 | 2022-02-18 | 江苏天士力帝益药业有限公司 | TSL-1502 compound pharmaceutical composition |
| CN115073544A (en) * | 2022-06-30 | 2022-09-20 | 上海应用技术大学 | PARP inhibitor pyrazoloquinine derivative and synthesis method thereof |
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| CN1876652A (en) * | 2000-04-24 | 2006-12-13 | 特瓦制药工业有限公司 | Zolpidem hemitartrate |
| CN101291654A (en) * | 2005-10-17 | 2008-10-22 | 马林克罗特公司 | Polymorph transformation of zolpidem in tablet matrix |
| CN101918385A (en) * | 2008-01-17 | 2010-12-15 | 安万特医药股份有限公司 | Crystalline forms of dimethoxy docetaxel and methods for preparing same |
| WO2011147296A1 (en) * | 2010-05-24 | 2011-12-01 | 苏州汉德森星湖生物制药有限公司 | Pyrazole derivatives |
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| CN1876652A (en) * | 2000-04-24 | 2006-12-13 | 特瓦制药工业有限公司 | Zolpidem hemitartrate |
| CN101291654A (en) * | 2005-10-17 | 2008-10-22 | 马林克罗特公司 | Polymorph transformation of zolpidem in tablet matrix |
| CN101918385A (en) * | 2008-01-17 | 2010-12-15 | 安万特医药股份有限公司 | Crystalline forms of dimethoxy docetaxel and methods for preparing same |
| WO2011147296A1 (en) * | 2010-05-24 | 2011-12-01 | 苏州汉德森星湖生物制药有限公司 | Pyrazole derivatives |
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