WO2013166966A1

WO2013166966A1 - Polymorphs of flourine-containing deuterium-substituted omega-diphenylurea or salts thereof

Info

Publication number: WO2013166966A1
Application number: PCT/CN2013/075343
Authority: WO
Inventors: 冯卫东
Original assignee: 苏州泽璟生物制药有限公司
Priority date: 2012-05-10
Filing date: 2013-05-08
Publication date: 2013-11-14
Also published as: CN103387536A; CN103387536B

Abstract

Provided are polymorphs of flourine-containing deuterium-substituted omega-diphenylurea or of salts thereof; more specifically, polymorphs of 4-(4-(3-(4-chlorine-3-(trimethyl)phenyl)acylurea)-3-fluorine-phenoxyl)-2-(N-1',1',1'-trideuteromethyl)picolinamide, comprising a polymorph I thereof, a polymorph II thereof, and a polymorph III of a p-toluenesulfonate thereof. Said polymorphs are suitable for use in the preparation of pharmaceutical compositions that inhibit phosphokinase (such as raf kinase).

Description

Polymorph of fluorine-containing deuterated ω-diphenylurea or a salt thereof

The present invention belongs to the field of medicine, and in particular to a polymorph of a fluorine-containing deuterated ω-diphenylurea or a salt thereof, and more particularly, to 4-(4-(3-(4-chloro-)- Polymorphic form of 3-(trifluoromethyl)phenyl]acylurea)-3-fluoro-phenoxy)-2-(indenylfluorene, fluorene, fluorene-tris-methyl)pyridineamide or a salt thereof Background technology

4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl) ureide)-3-fluoro-phenoxy)-2-( Ν-Γ, Γ, Γ-氘4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)3-f uorophenoxy)-2-(N- , , -trideuteromethyl)picolinamide), structure as Formula I does not.

The compound of formula I has the formula C ₂₁ H ₁₂ D ₃ ClF ₄ N ₄ O ₃ and has a molecular weight of 485.83, which is a white to off-white crystalline powder; odorless; tasteless. Very soluble in dimethyl sulfoxide or dimethylformamide, slightly soluble in methanol, slightly soluble in acetone, absolute ethanol or glacial acetic acid, almost insoluble in water, melting point 224~230 °C.

The compound of formula I is a compound which inhibits raft敫 enzyme and is suitable for the preparation of a medicament for the treatment of cancer and related diseases. However, all of the compounds currently used for the preparation of the corresponding drugs are amorphous compounds, and polymorphs of the compounds of the formula I have not yet been developed.

Therefore, it is highly desirable to develop polymorphs of the compounds of formula I. Summary of the invention

It is an object of the present invention to provide a series of 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl] ureide)-3-fluoro-phenoxy)-2-(oxime) a polymorph of hydrazine, hydrazine, hydrazine-tris-methyl)pyridine amide or a salt thereof. In a first aspect of the invention, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof Polymorph,

I

In another preferred embodiment, the pharmaceutically acceptable salt is p-toluenesulfonate.

In another preferred embodiment, the polymorph is a polymorph I of the compound of formula I, wherein the polymorph I has one or two X-ray powders selected from the group consisting of Diffraction characteristic peaks: 7.224 ± 0.2 °, and 14.507 ± 0.2

In another preferred embodiment, the polymorph I further has one or two X-ray powder diffraction characteristic peaks selected from the group consisting of: 13·363±0·2 ^ο , 17.192±0.2°, 禾卩19·779±0·2 ^ο .

In another preferred embodiment, the polymorph I has an X-ray powder diffraction pattern (X PD) substantially as shown in Figure 2a.

In another preferred embodiment, the differential scanning calorimetry pattern of the polymorph I has a maximum peak at 211.8-214.1 °C.

In another preferred embodiment, the polymorph I has a differential scanning calorimetry (DSC) substantially as shown in Figure 2b.

In another preferred embodiment, the polymorph is a polymorph II of a compound of formula I, wherein the polymorph II has one or more X-ray powders selected from the group consisting of Diffraction characteristic peaks: 22.323±0.2°, 24.199±0.2°, and 卩24·830±0·2 ^ο .

In another preferred embodiment, the polymorph II further has one or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 18·573±0·2 ^ο , 21.671±0.2°, 23.507± 0.2°, and 25·166±0·2 ^ο .

In another preferred embodiment, the polymorph II has an X-ray powder diffraction pattern substantially as shown in FIG.

(X PD).

In another preferred embodiment, the differential scanning calorimetry pattern of the polymorph II has a maximum peak at 196.2-198.6 °C.

In another preferred embodiment, the polymorph II has a differential scanning calorimetry (DSC) substantially as shown in Figure lb.

In another preferred embodiment, the polymorph is a polymorph III of p-toluenesulfonate of the compound of formula I, wherein the polymorph III has one or two selected from the group consisting of The X-ray powder diffraction characteristic peak of the group: 4.476±0.2°, and the 卩13·357±0·2 ^ο .

In another preferred embodiment, the polymorph III further has one or more X-ray powder derivatives selected from the group consisting of The characteristic peaks are: 16·517±0·2 ^ο , 18.037±0.2°, 21·786±0·2.禾卩22·990±0·2 ^ο .

In another preferred embodiment, the polymorph III has an X-ray powder diffraction pattern substantially as shown in Figure 3a.

In another preferred embodiment, the differential scanning calorimetry pattern of the polymorph III has a maximum peak at 239.5-241.7 °C.

In another preferred embodiment, the polymorph III has a differential scanning calorimetry pattern substantially as shown in Figure 3b. In another preferred embodiment, the p-toluenesulfonate of the compound of formula I is 1/1 p-toluenesulfonate, wherein the molar ratio of the compound of formula I to p-toluenesulfonic acid is 1:1.

In a second aspect of the invention, there is provided the use of a polymorph according to the first aspect of the invention for the preparation of a pharmaceutical composition for inhibiting a phosphokinase such as raf kinase.

In another preferred embodiment, the pharmaceutical composition is for the treatment and prevention of cancer.

In a third aspect of the invention, there is provided a pharmaceutical composition comprising:

(a) a polymorph according to the first aspect of the invention; and

(b) a pharmaceutically acceptable carrier.

In a fourth aspect of the invention, there is provided a process for the preparation of a polymorph according to the first aspect of the invention, which comprises the steps of: pharmaceutically acceptable a compound of formula I or a compound of formula I The accepted salt is recrystallized in an inert solvent to obtain the polymorph described in the first aspect of the invention.

In another preferred embodiment, the process for preparing the polymorph I comprises the steps of: recrystallizing the polymorph II obtained above in methanol to obtain the polymorph I.

In another preferred embodiment, the method for preparing the polymorph III comprises the steps of: recrystallizing the polymorph I obtained above and p-toluenesulfonic acid in an inert solvent to obtain the polymorph. Item III. It is to be understood that within the scope of the present invention, the various technical features of the present invention and the technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here. DRAWINGS

Panel la shows the X-ray powder diffraction pattern of the polymorph II of Example 1.

Figure lb shows a differential scanning calorimetry diagram of Polymorph II of Example 1.

Figure lc shows an NMR chart of the polymorph II of Example 1.

Figure 2a shows an X-ray powder diffraction pattern of the polymorph I of Example 2. Figure 2b shows a differential scanning calorimetry diagram of the polymorph I of Example 2.

Figure 2c shows an NMR chart of the polymorph I of Example 2.

Figure 3a shows an X-ray powder diffraction pattern of Polymorph III of Example 3.

Figure 3b shows a differential scanning calorimetry diagram of the polymorph III of Example 3.

Figure 3c shows an NMR chart of the polymorph III of Example 3. detailed description

The inventors have unexpectedly discovered 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl) ureide)-3-fluoro-phenoxy) by long-term and intensive research. a plurality of polymorphs of -2-(Ν-Γ, Γ, Γ-tridemethyl) pyridine amide or a salt thereof, which is high in purity and very stable, and is suitable for use in the preparation of a phosphoric acid inhibiting compound A pharmaceutical composition of a kinase (such as raft chymase) is more advantageous for treating diseases such as cancer. In addition, the polymorph of the present invention is difficult to lift, easy to collect, and wasteful in the process of manufacturing a drug such as dispensing. And to help protect the health of the operator. On this basis, the inventors have completed the present invention. As used herein, "compound of formula I" refers to 4-(4-(3-(4)) having the structural formula I. -Chloro-3-(trifluoromethyl)phenyl]urea)-3-fluoro-phenoxy)-2-(indenofluorene, anthracene, fluorene-tris-methyl)pyridineamide. Polymorph Object

The solid does not exist in an amorphous form or in a crystalline form. In the case of a crystalline form, the molecules are positioned within the three-dimensional lattice lattice. When a compound crystallizes out of a solution or slurry, it can crystallize in different spatial lattices (this property is called "polymorphism"), forming crystals with different crystalline forms, and these various crystalline forms are It is called "polymorph". Different polymorphs of a given material may differ from each other in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystalline form, bulk mode, fluidity, and/or solid state stability. Crystallization

The solubility limit of the compound of interest can be exceeded by operating the solution to complete crystallization on a production scale. This can be done in a number of ways, for example by dissolving the compound at relatively high temperatures and then cooling the solution below the saturation limit. Alternatively, the volume of the liquid can be reduced by boiling, atmospheric evaporation, vacuum drying or by some other means. The solubility of the compound of interest can be lowered by adding an antisolvent or a solvent having a low solubility in the compound or a mixture of such a solvent. Another alternative It is to adjust the pH to reduce the solubility. For a detailed description of crystallization, see Crystallization, Third Edition, JW Mullens, Butterworth-Heineman Ltd., 1993, ISBN 075061 1294.

If salt formation is desired to occur simultaneously with crystallization, if the salt is less soluble than the starting material in the reaction medium, the addition of a suitable acid or base can result in direct crystallization of the desired salt. Also, in the medium in which the final desired form is less soluble than the reactant, the completion of the synthesis reaction allows the final product to crystallize directly.

Optimization of crystallization can include seeding the crystal in a desired form with the crystal as a seed. In addition, many crystallization methods use a combination of the above strategies. One embodiment is to dissolve the compound of interest in a solvent at elevated temperatures, followed by controlled addition of an appropriate volume of anti-solvent to bring the system just below the level of saturation. At this point, seed crystals of the desired form can be added (and the integrity of the seed crystals maintained) and the system cooled to complete crystallization.

As used herein, the term "room temperature" generally refers to 4-30 °C, preferably 20 ± 5 °C. Polymorph of the invention

As used herein, the term "polymorph of the invention" includes a polymorph of a compound of formula I or a salt thereof (e.g., p-toluenesulfonate), and also includes different polymorphs of a compound of formula I.

Preferably, it is a polymorph I or polymorph II of a compound of formula I, or a polymorph III of a 1/1 p-toluenesulfonate of a compound of formula I, wherein the compound of formula I and p-toluenesulfonic acid The molar ratio is 1:1. Identification and properties of polymorphs

After preparing the polymorph of the compound of formula I, the present invention has been studied in a variety of ways and instruments as follows.

X-ray powder diffraction

Methods for determining X-ray powder diffraction of crystalline forms are known in the art. For example, using a Rigaku D/max 2550VB/PC model X-ray powder diffractometer, a copper radiation target is used to acquire the spectrum at a scanning speed of 2° per minute.

The polymorph of the compound of formula I of the present invention has a specific crystal form and has a specific characteristic peak in an X-ray powder diffraction (XPD) pattern.

(1) Polymorph I

The polymorph I has one or two X-ray powder diffraction characteristic peaks selected from the group consisting of: 7.224±0.2°, and 14.507±0.2 In another preferred embodiment, the polymorph I further has one or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 13·363±0·2 ^ο , 17.192±0.2°, Wo 19·779±0·2 ^ο .

In another preferred embodiment, the polymorph I has an X-ray powder diffraction pattern substantially as shown in Figure 2a. (2) Polymorph II

The polymorph II has one or more X-ray powder diffraction characteristic peaks selected from the group consisting of 22·323±0·2 ^ο , 24·199±0·2 ^ο , and 卩24·830± 0·2 ^ο .

In another preferred embodiment, the polymorph II has an X-ray powder diffraction pattern substantially as shown in Figure la.

(3) Polymorph III

The polymorph III has one or two X-ray powder diffraction characteristic peaks selected from the group consisting of: 4.476 ± 0.2 °, and 13.357 ± 0.2

In another preferred embodiment, the polymorph III further has one or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 16·517±0·2 ^ο , 18.037±0.2°, 21· 786±0·2.禾卩22·990±0·2 ^ο .

In another preferred embodiment, the polymorph III has an X-ray powder diffraction pattern substantially as shown in Figure 3a. Differential scanning calorimetry

Also known as "differential calorimetric scanning analysis" (DSC), it is a technique for measuring the relationship between the energy difference between a test substance and a reference material and temperature during heating. The position, shape and number of peaks on the DSC map are related to the nature of the material and can therefore be used qualitatively to identify the substance. This method is commonly used in the art to detect various parameters such as phase transition temperature, glass transition temperature, and heat of reaction of a substance.

DSC assay methods are known in the art. For example, a DSC scan of the crystal form can be obtained by using a NETZSCH DSC 204 F1 differential scanning calorimeter at a temperature increase rate of 10 ° C per minute from 25 ° C to 250 ° C.

The polymorph of the compound of formula I of the present invention has a specific characteristic peak in a differential calorimetric scanning (DSC) chart.

(1) Polymorph I

The differential scanning calorimetry pattern of the polymorph I has a maximum peak at 211.8-214.rC. In another preferred embodiment, the polymorph I has a differential scanning calorimetry (DSC) substantially as shown in Figure 2b.

(2) Polymorph II

The differential scanning calorimetry spectrum of the polymorph II has a maximum peak at 196.2-198.6 °C.

(3) Polymorph III

The differential scanning calorimetry pattern of the polymorph III has a maximum peak at 239.5-241.7 °C.

In another preferred embodiment, the polymorph III has a differential scanning calorimetry pattern substantially as shown in Figure 3b. Nuclear magnetic resonance

Nuclear magnetic resonance (NMR) can also be employed to aid in the determination of crystal structure, the method of which is known in the art. The invention preferably employs Bruker Avance III plus-400 MHz.

Active ingredient

As used herein, the term "active ingredient" or "active compound" refers to a polymorph of the invention, ie a polymorph of a compound of formula I, and of course a polymorph of a pharmaceutically acceptable salt thereof. . The pharmaceutically acceptable salt is, for example but not limited to, p-toluenesulfonate. Pharmaceutical composition and method of administration

Since the polymorph of the present invention has excellent inhibitory activity against phosphokinase (Kinase M column such as rafi敫 enzyme, the polymorph of the present invention and the pharmaceutical composition containing the polymorph of the present invention as a main active ingredient It can be used for the treatment, prevention and alleviation of diseases mediated by phosphokinase (Kinase M column such as raft敫 enzyme. According to the prior art, the polymorph of the invention can be used for the treatment of the following diseases: cancer, cardiovascular disease, obesity, Diabetes and so on.

The pharmaceutical compositions of the present invention comprise a polymorph of the invention in a safe and effective amount and a pharmaceutically acceptable excipient or carrier. By "safe and effective amount" is meant that the amount of the compound (or polymorph) is sufficient to significantly improve the condition without causing serious side effects. In general, the pharmaceutical composition contains from 1 to 2000 mg of the polymorph/agent of the invention, more preferably from 10 to 200 mg of the polymorph/agent of the invention. Preferably, the "one dose" is a capsule or a tablet.

"Pharmaceutically acceptable carrier" means: one or more compatible solid or liquid fillers or gels Substances, which are suitable for human use and must be of sufficient purity and of sufficiently low toxicity. By "compatibility" it is meant herein that the components of the composition are compatible with the active ingredients of the present invention and between them without significantly reducing the efficacy of the active ingredients. Examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid). , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), moist Wet agents (such as sodium decyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The mode of administration of the polymorph or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include, but are not limited to, oral, intratumor, rectal, parenteral (intravenous, intramuscular or subcutaneous), And topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) moisturizing An agent, for example, glycerin; (d) a disintegrant, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; f) absorption accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc , calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or a mixture thereof. In capsules, tablets and pills, the dosage form may also contain a buffer.

Solid dosage forms such as tablets, troches, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric materials and waxy materials. The active ingredient may also form a microcapsule form with one or more of the above excipients as necessary.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.

In addition to these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, Sweeteners, flavorings and spices.

In addition to the active ingredient, the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar or a mixture of these and the like.

Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms of the polymorphs of the invention for topical administration include ointments, powders, patches, propellants and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.

The polymorphs of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

When a pharmaceutical composition is used, a safe and effective amount of the polymorph of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective effective dose for a person weighing 60 kg. In general, the daily dose is usually from 1 to 2000 mg, preferably from 20 to 500 mg. Of course, specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician. The main advantages of the invention are:

1. A series of novel 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl) ureide)-3-fluoro-phenoxy)-2-(Ν- a polymorph of a hydrazine, a hydrazine, a hydrazine-triterpene methyl) pyridine amide or a salt thereof, wherein the polymorph I and the polymorph II of the compound of the formula I, and the p-methyl group of the compound of the formula I Polymorph III of the besylate salt.

2. The use of the polymorph is also provided for the preparation of a pharmaceutical composition for inhibiting a phosphokinase (e.g., raft chymase) for use in the treatment of diseases such as cancer. The invention will be further elucidated below in conjunction with specific implementations. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or in accordance with the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated. The materials used in the present invention are commercially available unless otherwise specified. Example 1

4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl) ureide)-3-fluoro-phenoxy)-2-(-1',1',1'- Triterpenoid methyl) Polymorph II of picolinamide

50 g of methyl 4-chloro-2-picolinate was dissolved in a 250 mL tetrahydrofuran three-necked flask, and 31 g of deuterated methylamine hydrochloride and 80 g of anhydrous potassium carbonate were respectively added, and the mixture was stirred at 25 ° C for 20 hours and then added to 250 mL of water. And lOOmL methyl tert-butyl ether, stirred and layered, separated, and the aqueous phase was extracted with 100 mL of methyl t-butyl ether. The organic phase was combined and dried, and the solvent was evaporated under reduced pressure to give pale yellow 4-chloro-N- 48 g of a solution of pyridyl-2-carboxamide.

15 g of potassium tert-butoxide was suspended in 50 mL of a solution of N,N-dimethylacetamide, and 3-fluoro-4-amino-phenol (16 g) of N, N was slowly added dropwise at 0 to 5 degrees. - dimethylacetamide (50 mL) solution, stirred at room temperature for 20 minutes, warmed to 100 ° C and slowly added dropwise N,N of 4-chloro-N-deuterated methylpyridine-2-carboxamide (17 g) - Dimethylacetamide (50 mL), stirring was continued for 0.5 hours, cooled to 25 ° C, and 500 mL of ethyl acetate was added to the reaction mixture, and the mixture was stirred for 0.5 hour, and the inorganic salt was removed by filtration, using 500 mL of water. Washed, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. <RTI ID=0.0>> -N-deuterated methylpyridine-2-carboxamide solid 20 g.

13 g of 4-chloro-3-trifluoromethylphenylisocyanate was dissolved in 70 mL of ethyl acetate at 25 ° C, and 14 g of 4-(4-amino-3-fluoro-phenoxy)- A solution of N-deuterated methylpyridine-2-carboxamide in 350 mL of ethyl acetate was slowly added dropwise to the above solution, and stirred at 25 ° C for 20 hours. The reaction was filtered and washed twice with 20 mL of ethyl acetate to afford Brown solid.

The sample was confirmed by 1H NMR, X-ray powder diffraction, DSC, and the like. 1H NM (DMSO-d6, 400 MHz): δ 7.06-7.10(m, 1H), 7.19(dd, J = 2.4Hz, 5.6Hz, 1H), 7.35(dd, J = 2.8Hz, 12Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.63 (m, 2H), 8.14 (br, 1H) 8.17 (t, J = 8.8 Hz, 1H), 8.53 (d, J = 5.6 Hz, 1H), 8.75 (d, J = 1.6Hz, 1H), 8.78(br, 1H), 9.54(br, 1H).

The X-ray powder diffraction pattern is shown in la, the parameters of each peak are shown in Table 1, the differential scanning calorimetry (DSC) is shown in Figure lb, and the 1H NMR spectrum is shown in lc.

Table 1

Peak number 2Θ(°) Peak height Relative intensity (1%) Peak number 2Θ(°) Peak height Relative intensity (1%)

1 6.627 907 3.81 22 24.199 23808 100.00

2 9.828 31 16 13.09 23 24.830 1 1204 47.06

3 10.778 1495 6.28 24 25.166 3926 16.49

4 11.388 3255 13.67 25 26.548 1805 7.58 5 12.336 4600 19.32 26 28.327 1 1 17 4.69

6 12.938 860 3.61 27 29.173 2725 1 1.45

7 13.267 1910 8.02 28 30.004 3103 13.03

8 13.599 3263 13.71 29 31.580 1732 7.27

9 14.230 2782 1 1.69 30 31.974 940 3.95

10 14.761 2998 12.59 31 32.726 1747 7.34

1 1 15.451 3245 13.63 32 33.869 1276 5.36

12 15.969 1245 5.23 33 34.071 1255 5.27

13 17.032 1270 5.33 34 34.819 970 4.07

14 17.745 2310 9.70 35 36.795 1 1 13 4.67

15 18.573 5092 21.39 36 37.305 993 4.17

16 19.067 21 15 8.88 37 38.213 802 3.37

17 19.974 2053 8.62 38 38.845 890 3.74

18 21.671 6374 26.77 39 39.498 914 3.84

19 22.323 12716 53.41 40 40.583 1069 4.49

20 23.054 2736 1 1.49 41 42.617 813 3.41

21 23.507 5938 24.94 42 43.823 779 3.27

Example 2

4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl) ureide)-3-fluoro-phenoxy)-2-(7V-l',l',l' Polymorph I of the triterpene methyl) pyridine amide

500 mg of the polymorph II prepared in Example 1 was added to 20 ml of acetone, stirred and dissolved, and 15 ml of water was added dropwise at room temperature to precipitate a solid, which was stirred for 30 minutes, and filtered, and the obtained solid was washed with 10 ml of water. Dry at 30 ° C for 16 hours under vacuum. The sample was confirmed by 1H NMR, X-ray powder diffraction, DSC, and the like to give the title compound 200 mg.

1H NM ( DMSO-d6, 400 MHz ): δ 7.06-7.10 (m, 1H), 7.19 (dd, J = 2.4 Hz, 5.6 Hz, 1H), 7.35 (dd, J = 2.8 Hz, 12 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.63 (m, 2H), 8.14 (br, 1H), 8.17 (t, J = 8.8 Hz, 1H), 8.53 (d, J = 5.6 Hz, 1H), 8.75 (d, J = 1.6 Hz, 1H), 8.78 (br, 1H), 9.54 (br, 1H).

The X-ray powder diffraction pattern is shown in Figure 2a, and the parameters of each peak are shown in Table 2. Differential Scanning Calorimetry (DSC) is shown in Figure 2b, and 1H NMR is shown in Figure 2c.

Table 2

Example 3

4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl) ureide)-3-fluoro-phenoxy)-2-(Ν-1',1',1' -Trisylmethyl) Pyridylamide 1/1 p-toluenesulfonate polymorph III

The polymorph I (10 g) obtained in Example 2 was suspended in 150 mL of ethanol, 1.4 g of p-toluenesulfonic acid monohydrate was added, the temperature was raised to 80 ° C until clarification, and the filtrate was heated to reflux to clarify. A solution of 3.4 g of p-toluenesulfonic acid monohydrate in 10 mL of ethanol was added, and the mixture was stirred under constant temperature for 30 min, and then cooled to 25 ° C, and filtered to give 12 g of the title compound. Sampling detection 1H NMR, X-ray powder diffraction, DSC:.

From the nuclear magnetic data, the molar ratio of the compound of the formula I to p-toluenesulfonic acid was 1:1.

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£t£SLO/£lOZSLJ/∑Jd 99699l/CT0Z OAV 24 24.907 1786 5.56 50 41.875 1844 5.74

25 25.597 1690 5.26 51 44.363 1403 4.37

26 26.087 1486 4.62 Example 4 4-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl) ureide)-3-fluoro-phenoxy)-2-(Ν-1 Stability of polymorph I of ',1',1'-triterpene methyl)pyridine amide

After an accelerated test of 1-6 months (test conditions 40 ° C, 75% H), the results show that the crystal form of polymorph I is very stable; and compared with the newly prepared (0 month) polymorph In the case of the substance I, the impurity content in the polymorph I was changed by less than 15%. Example 5 Pharmaceutical Composition

4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl) ureide)-3-fluoro-phenoxy)-2-(Ν-Γ,Γ,Γ-三氘Polymorph of methyl iodide pyridine amide 1 (Example 2) 20 g

Starch 140g

Microcrystalline cellulose 60g

The above materials were uniformly mixed according to a conventional method, and then filled into ordinary gelatin capsules to obtain 1000 capsules. It can be seen that the various polymorphs described herein are very stable and are highly suitable for use in pharmaceutical compositions. Further, in the process of manufacturing a drug such as dispensing, the polymorph of the present invention is difficult to lift, is easy to collect, is not easy to cause waste, and contributes to protecting the health of the operator. All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the the In addition, it is to be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims

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1. A crystalline form of formula I,

I

2. The polymorph according to claim 1, wherein the polymorph is a polymorph I of a compound of formula I, wherein the polymorph I has one or Two X-ray powder diffraction characteristic peaks selected from the group consisting of 7.224±0.2° and Hessian 14.507±0.2°.

3. The polymorph according to claim 2, wherein the differential scanning calorimetry pattern of the polymorph I has a maximum peak at 211.8-214.

4. The polymorph according to claim 1, wherein the polymorph is a polymorph II of a compound of formula I, wherein the polymorph II has one or A plurality of X-ray powder diffraction characteristic peaks selected from the group consisting of 22·323±0·2 ^ο , 24.199±0.2°, and ·24·830±0·2 ^ο .

5. The polymorph according to claim 4, wherein the differential scanning calorimetry pattern of the polymorph II has a maximum peak at 196.2-198.6 °C.

6. The polymorph according to claim 1, wherein the polymorph is a polymorph of p-toluenesulfonate of the compound of formula I, wherein the polymorph The substance III has 1 or 2 X-ray powder diffraction characteristic peaks selected from the group consisting of 4.476±0.2°, and 13.357±0.2°.

7. The polymorph according to claim 6, wherein the differential scanning calorimetry pattern of the polymorph III has a maximum peak at 239.5-241.7 °C.

Use of a polymorph according to any one of claims 1-7, characterized in that it is used for the preparation of a pharmaceutical composition for inhibiting phosphokinase.

9. Use according to claim 8, wherein the pharmaceutical composition is for the treatment and prevention of cancer.

10. A pharmaceutical composition, comprising:

(a) the polymorph according to any one of claims 1 to 7;

(b) a pharmaceutically acceptable carrier.

11. A process for the preparation of a polymorph according to any one of claims 1 to 7, which comprises the step of: a compound of formula I or a pharmaceutically acceptable salt of a compound of formula I Recrystallization in an inert solvent to obtain the polymorph according to any one of claims 1-7.