CN106518773A - Crystalline form of androgen receptor inhibitor and preparation method thereof - Google Patents
Crystalline form of androgen receptor inhibitor and preparation method thereof Download PDFInfo
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- CN106518773A CN106518773A CN201610812288.1A CN201610812288A CN106518773A CN 106518773 A CN106518773 A CN 106518773A CN 201610812288 A CN201610812288 A CN 201610812288A CN 106518773 A CN106518773 A CN 106518773A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
- C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention relates to a crystalline form of an androgen receptor inhibitor and a preparation method thereof, in particular to a type II crystal of (S)-4-(3-(4-(2,3-hydroxypropoxy)phenyl)-4,4-dimethyl-5-carbonyl-2-trifluoromethyl-1-yl)-2-(trifluoromethyl)benzonitrile (a compound shown as a formula (I)) and a preparation method thereof. The method comprises the following steps: 1) adding the compound shown as the formula (I) of any crystalline form or an amorphous form into a proper amount of organic solvent, and crystalizing after dissolved clarification, wherein the solvent is selected from methanol or ethanol; 2) filtering the crystal, washing and drying. The type II crystal of the compound shown as the formula (II) has the advantages of excellent chemical stability and crystalline form stability, and the used crystal solvent has low toxicity and low residue, and can be better applied to clinical therapy. The formula is shown in the description.
Description
Technical field
The present invention relates to a kind of crystal form of androgen receptor inhibitor and preparation method thereof.The specific present invention is related to
And (S) -4- (3- (4- (2,3- dihydroxy propoxyl group) phenyl) -4,4- dimethyl -5- carbonyl -2- thiocarbamoyl imidazole quinoline -1- bases) -2-
New crystal form of (trifluoromethyl) benzonitrile and preparation method thereof.
Background technology
Prostate cancer (prostate cancer, PCa) is to betide the malignant tumour in human male prostate tissue, before being
The result of row gland acinar cells exception random growth.The differentiation and growth of normal prostatic epithelium cell and sending out for prostate cancer
Exhibition depends on male sex hormone, male sex hormone to be mainly synthesized in testis, constitutes about 80～90%.The male sex hormone of synthesis is entered
Androgen receptor (Androgen receptor, AR) is combined after cell, causes heat shock protein (HSP) to dissociate simultaneously from AR
Make AR enter nucleus, activate multiple downstream genes, including prostate specific antigen (PSA).The prostate cancer of early stage is to male
Hormone-sensitive, implements the development that orchiectomy (castration) can substantially suppress prostate cancer.But castration operation is with certain
It is ageing, many patients are experienced from male sex hormone dependence to androgen-independent after castration for a period of time
Transformation, for antiandrogen treats no longer valid, develops into Androgen Independent Prostate Cancer (androgen
Independent prostate cancer, AIPC), and the activation that still AR signal paths intracellular with PCa occur of AlPC has
Important relationship.
First generation medicine for the purpose of suppressing AR active have Bicalutamide (Bicalutamide or Casodex) and fluorine he
Amine (Flutamide).There is MDV3100 and ARN-509 for the second generation AR antagonist pharmaceuticals of AlPC treatments.MDV3100 is generation
In boundary, the non-steroid AR antagonist pharmaceuticals of the first second generation, are approved by the FDA in the United States listing in by the end of August, 2012 in.MDV-3100
It is higher than Bicalutamide to the affinity of AR 5-8 times, can be by suppressing AR activity so as to suppress the life of AlPC mouse and human tumour
It is long, and there is no the effect for promoting growth of tumour cell.
WO2014036897A1 discloses the new AR antagonists of a class, including compound, the compound shown in formula (I)
External activity is slightly better than MDV3100, and hERG inhibiting rates further improve (IC50：24.83uM), to five Main Subtypes of CYP450
The suppression half-life be all higher than 50uM, same dosage is suitable with MDV3100 for internal exposed amount with big raticide under solvent, dog medicine generation
Exposed amount reaches more than six times of MDV3100 in vivo.Formula (I) compound only has a chiral centre, and its chiral raw material is simple and easy to get,
Synthesis difficulty is substantially reduced.In addition, formula (I) compound is in the no AR agonist activities of 3uM and 10uM, and in Mice brain tissues
Drug concentration is far below MDV3100 compounds with blood concentration ratio, and the possibility for epilepsy side effect occur is less, therefore formula
(I) compound has wide clinical landscapes.
But WO2014036897A1 does not further investigate the crystal form of the compound.It is as well known to those skilled in the art, it is medicinal
The crystalline structure of active component often have influence on the difference of the chemical stability of the medicine, crystallization condition and condition of storage have can
The change of the crystalline structure of compound can be caused, sometimes can also be along with the crystal formation for producing other forms.In general, it is unformed
Drug products do not have well-regulated crystalline structure, often with other defects, such as product stability is poor, and crystallization is thinner, mistake
Filter is more difficult, easily lumps, poor fluidity etc..Therefore, each side's surface properties for improving above-claimed cpd are necessary, it would be desirable to
It is higher and possess the novel crystal forms of good chemical stability that crystal form purity is found in further investigation.
The content of the invention
The invention provides (S) -4- (3- (4- (2,3- dihydroxy propoxyl group) phenyl) -4,4- dimethyl -5- carbonyl -2-
Thiocarbamoyl imidazole quinoline -1- bases) -2- (trifluoromethyl) benzonitrile (as shown in formula (I)) new crystal form.
The series of crystallization product that compound shown in formula (I) is obtained under different crystallization conditions, enters to gained crystallized product
X- diffraction and DSC detections are gone, it is found that compound is under the crystallization condition of the present invention shown in formula (I), can obtain a kind of stable
Property good crystal formation, we are called the crystallization of II types.The DSC collection of illustrative plates of the II types crystallization in the application is displayed in 119 DEG C nearby to be had
Melting endothermic peak, X-ray powder diffraction collection as shown in figure 1, radiated using Cu-Ka, with 2 θ angles and interplanar distance (d values)
The X-ray powder diffraction collection of expression, wherein 4.63 (19.06), 7.37 (11.99), 9.25 (9.55), 10.91
(8.11), 11.48 (7.70), 12.40 (7.13), 13.05 (6.78), 13.73 (6.45), 15.03 (5.89), 16.04
(5.52), 16.96 (5.22), 17.87 (4.96), 19.03 (4.66), 19.45 (4.56), 20.59 (4.31), 21.87
(4.06), 22.50 (3.95), 23.11 (3.85), 23.53 (3.78), 23.96 (3.71), 25.43 (3.50), 27.00
(3.30), 27.60 (3.23), 29.77 (3.00) have characteristic peak.
Present invention also offers preparing (S) -4- (3- (4- (2,3- dihydroxy propoxyl group) phenyl) -4,4- dimethyl -5- carbonyls
Base -2- thiocarbamoyl imidazole quinoline -1- bases) -2- (trifluoromethyl) benzonitrile the crystallization of II types method, methods described includes following steps
Suddenly：
1) any crystal formation or compound shown in unformed formula (I) are added in appropriate organic solvent, heat it is molten it is clear after
Cooling crystallization, one or more in the solvent selected from methanol or ethanol；
2) filtering for crystallizing wash, be dried.
The method of recrystallization is not particularly limited, and can be carried out with common recrystallization operation method.For example, can be with original
The slowly cooling crystallization after organic solvent heating for dissolving of compound shown in material formula (I), it is after the completion of crystallization, dry through being filtered dry, you can
Crystallization required for obtaining.Specifically, the crystalline solid of institute's leaching is generally under reduced pressure, at 30～100 DEG C or so, excellent
It is vacuum dried under the heating condition for selecting 40～60 DEG C, can be just reached the effect for removing recrystallization solvent.
Determined by differential scanning calorimeter (DSC), X- diffracting spectrums, to compound crystalline solid shown in the formula (I) that obtains
Crystal formation research is carried out, while being detected to the dissolvent residual of gained crystallization.
Do not contain or only containing lower content according to compound II types crystallization shown in formula (I) prepared by the method for the present invention
Residual solvent, meets the limitation requirement of the relevant medical product residual solvent of NF regulation, thus the crystallization of the present invention can
Preferably to use as medicating active ingredients.
Jing research show, the present invention prepare formula (I) shown in compound II types crystallization illumination, high temperature, high humidity bar
Part stability inferior is good, and in grinding, pressure and under the conditions of being heated etc., stability of crystal form is good, disclosure satisfy that production and transport is stored up
The medicinal requirements deposited, stable processing technique repeats controllable, can adapt in industrialized production.
Description of the drawings
The X-ray powder diffraction collection of the crystallization of compound II types shown in Fig. 1 formulas (I).
The DSC collection of illustrative plates of the crystallization of compound II types shown in Fig. 2 formulas (I).
The X-ray powder diffraction collection of the crystallization of compound type III shown in Fig. 3 formulas (I).
The DSC collection of illustrative plates of the crystallization of compound type III shown in Fig. 4 formulas (I).
Specific embodiment
The present invention is explained in greater detail below with reference to embodiment, embodiments of the invention are merely to illustrate the skill of the present invention
Art scheme, and non-limiting the spirit and scope of the invention.
Experiment tester used
1st, DSC spectrums
INSTRUMENT MODEL：MettlerToledo DSC 1Staree System
Purge gass：Nitrogen
Heating rate：10.0℃/min
Temperature range：40～250 DEG C
2nd, x-ray diffraction pattern
INSTRUMENT MODEL：Bruker D8Focus X-ray powder diffraction instrument
Ray：Monochromatic Cu-K alpha rays (λ=1.5406)
Scan mode：θ/2 θ, sweep limits：2～40 °
Voltage：40KV, electric current：40mA
Embodiment 1
Take compound shown in (1.0g, 2.09mmol) formula (I) (by WO2014036897A1 provide method prepare) in
In 25ml single port bottles, 5.0ml methyl alcohol is added, be heated to reflux molten clear, continuation backflow 10min, cooling, stirring and crystallizing, suction filtration are dried
Solid 516mg is obtained, yield is 51.6%.The X-ray diffraction spectrogram of the crystallized sample is shown in Fig. 1.The crystallization is about 4.63
(19.06), 7.37 (11.99), 9.25 (9.55), 10.91 (8.11), 11.48 (7.70), 12.40 (7.13), 13.05
(6.78), 13.73 (6.45), 15.03 (5.89), 16.04 (5.52), 16.96 (5.22), 17.87 (4.96), 19.03
(4.66), 19.45 (4.56), 20.59 (4.31), 21.87 (4.06), 22.50 (3.95), 23.11 (3.85), 23.53
(3.78) there is characteristic peak, 23.96 (3.71), 25.43 (3.50), 27.00 (3.30), 27.60 (3.23), 29.77 (3.00) places.
DSC spectrograms are shown in Fig. 2, have sharp 119 DEG C of endothermic peak of melting, this crystal formation is defined as II crystal formations.
Embodiment 2
Compound (preparing by embodiment 1) shown in (1.0g, 2.09mmol) formula (I) is taken in 25ml single port bottles, is added
5.0ml ethanol, is heated to reflux molten clear, continues backflow 10min, cooling, stirring and crystallizing, suction filtration, dry solid 633mg, yield
For 63.3%.Its X- diffraction and DSC collection of illustrative plates Jing researchs are compared, and determine that product is II crystal formations.
Embodiment 3
Repeat all operationss of WO2014036897A1 embodiments 44, by (R) -4- (3- (4- ((2,2- dimethyl -1,3-
Dioxolanes -4- bases) methoxyl group) phenyl) -4,4- dimethyl -5- ketone -2- thiocarbamoyl imidazole quinoline -1- bases) -2- (trifluoromethyl) benzene
Nitrile (2.2g, 4.20mmol) is dissolved in 100mL acetic acid, adds 50mL water, is warming up to 70 DEG C of stirring reactions 1h, reactant liquor decompression
Concentration removes acetic acid, adds 100mL water and 100mL ethyl acetate, and stratification, organic phase are washed with saturated sodium bicarbonate solution
Wash, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, with Silica gel chromatography, obtain compound I crystallization (1.1g,
55.0%).The Jing X-ray diffractions of the crystallized sample and DSC spectrograms Jing researchs are compared, it was demonstrated that not II crystal formations, are determined herein
Justice is III crystal formations.
Embodiment 4
Placement is divided by the II types crystallized sample obtained by embodiment 1 open respectively, is investigated at illumination (4500Lux), heating
(40 DEG C, 60 DEG C), the stability of sample under the conditions of high humidity (RH75%, RH90%).Sample time is investigated for 5 days and 10 days,
HPLC detections purity is shown in Table 1.
Shown in 1. formula of table (I), the stability of compound II crystal form samples compares
Study on the stability result shows that compound II types crystallized sample is under conditions of open placement shown in formula (I), Jing light
Having good stability under according to, high temperature and super-humid conditions.
Embodiment 5
As obtained in 1 method of embodiment the crystallization of compound II types shown in formula (I) will be ground, heat and compressing tablet process,
Result of study shows stable crystal form, and detailed experimental data is referring to table 2 below.
The special stability study of compound II crystal formations shown in 2. formula of table (I)
Claims (4)
1. the II types of compound as shown in formula (I) are crystallized, it is characterised in that：Radiated using Cu-Ka, obtained with 2 θ angles and crystal face
The X-ray powder diffraction collection that spacing is represented, the crystallization have X-ray powder diffraction collection as shown in Figure 1, wherein exist
About 4.63 (19.06), 7.37 (11.99), 9.25 (9.55), 10.91 (8.11), 11.48 (7.70), 12.40 (7.13),
13.05 (6.78), 13.73 (6.45), 15.03 (5.89), 16.04 (5.52), 16.96 (5.22), 17.87 (4.96), 19.03
(4.66), 19.45 (4.56), 20.59 (4.31), 21.87 (4.06), 22.50 (3.95), 23.11 (3.85), 23.53
(3.78), 23.96 (3.71), 25.43 (3.50), 27.00 (3.30), 27.60 (3.23), 29.77 (3.00) have characteristic peak
2. the method that one kind prepares the II types crystallization of the compound as shown in formula (I) according to claim 1, methods described bag
Include following step：
1) any crystal formation or compound shown in unformed formula (I) are added in appropriate organic solvent, molten clear rear crystallization is described
Solvent selected from methanol or ethanol；
2) filtering for crystallizing wash, be dried.
3. a kind of pharmaceutical composition, its contain II types crystallization of the compound as shown in formula (I) according to claim 1 and
Pharmaceutically acceptable carrier.
4. the II types of the compound as shown in formula (I) according to claim 1 are crystallized or medicine according to claim 3
Purposes of the composition in the medicine for preparing the treatment disease relevant with androgen receptor；The preferred prostate cancer of the disease.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510575521 | 2015-09-10 | ||
| CN2015105755214 | 2015-09-10 |
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| CN106518773A true CN106518773A (en) | 2017-03-22 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109912509A (en) * | 2017-12-13 | 2019-06-21 | 江苏恒瑞医药股份有限公司 | A kind of crystal form and preparation method thereof of androgen receptor inhibitor |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014036897A1 (en) * | 2012-09-04 | 2014-03-13 | 上海恒瑞医药有限公司 | Imidazoline derivatives, preparation methods thereof, and their applications in medicine |
-
2016
- 2016-09-09 CN CN201610812288.1A patent/CN106518773A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014036897A1 (en) * | 2012-09-04 | 2014-03-13 | 上海恒瑞医药有限公司 | Imidazoline derivatives, preparation methods thereof, and their applications in medicine |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109912509A (en) * | 2017-12-13 | 2019-06-21 | 江苏恒瑞医药股份有限公司 | A kind of crystal form and preparation method thereof of androgen receptor inhibitor |
| CN112174895A (en) * | 2017-12-13 | 2021-01-05 | 江苏恒瑞医药股份有限公司 | Crystal form of androgen receptor inhibitor and preparation method thereof |
| CN112300076A (en) * | 2017-12-13 | 2021-02-02 | 江苏恒瑞医药股份有限公司 | Crystal form of androgen receptor inhibitor and preparation method thereof |
| CN109912509B (en) * | 2017-12-13 | 2021-02-26 | 江苏恒瑞医药股份有限公司 | Crystal form of androgen receptor inhibitor and preparation method thereof |
| CN112174895B (en) * | 2017-12-13 | 2022-06-21 | 江苏恒瑞医药股份有限公司 | Crystal form of androgen receptor inhibitor and preparation method thereof |
| CN112300076B (en) * | 2017-12-13 | 2022-10-25 | 江苏恒瑞医药股份有限公司 | Crystal form of androgen receptor inhibitor and preparation method thereof |
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