# Patent

## Title
Polymorphs of deuterated omega-diphenylurea or salts thereof

## Abstract

The invention relates to polymorphs of deuterated omega-diphenylurea or salts thereof. In particular, the invention provides polymorphs of 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)picolinamide or its salt, namely, polymorphs of the compound as shown in formula (I) or its salt. The polymorphs are suited for preparing the pharmaceutical composition used for inhibiting phosphokinase (such as raf kinases).

## Background
CROSS REFERENCE TO RELATED APPLICATION
This application is a divisional of U.S. patent application Ser. No. 14/415,340, filed on Jan. 16, 2015, entitled “POLYMORPHS OF DEUTERATED OMEGA-DIPHENYLUREA OR SALTS THEREOF,” which is a Section 371 of International Application No. PCT/CN2013/079469, filed Jul. 16, 2013, which was published in the Chinese language on Jan. 23, 2014, under International Publication No. WO 2014/012480 A1, the disclosure of which is incorporated herein by reference.


TECHNICAL FIELD
The present invention relates to the field of medicine, and particularly, relates to polymorphs of deuterated omega-diphenylurea or salts thereof, and more particularly, relates to polymorphs of 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)pico linamide or salts thereof.
BACKGROUND
The structure of 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)picolinamide is shown as formula I.




The compound of formula I, with a molecular formula of C21H13D3ClF3N4O3 and a molecular weight of 467.84, is a white or off-white crystal powder, odorless and tasteless. It is very soluble in dimethyl sulfoxide or dimethyl formamide, sparingly soluble in methanol, slightly soluble in acetone, anhydrous ethanol and glacial acetic acid, and practically insoluble in water.
The compound of formula I belongs to compounds that inhibit raf kinase, and is suitable for preparing drugs for the treatment of cancer and other related diseases. Different crystal forms of a drug might affect its dissolution, absorption in vivo, thereby affecting its clinical therapeutic effect and safety to a certain extent. In particular, for some slightly soluble solid or semisolid oral preparations, the influence of crystal forms is huge. There are no studies on polymorphs of compound I up to now, and no polymorphs of compound I have been developed yet.
Therefore, it is necessary to develop the polymorphs of compound I.
SUMMARY OF INVENTION
The purpose of the present invention is to provide polymorphs of compound I or pharmaceutically acceptable salts thereof, or solvates thereof.
In the first aspect, polymorphs of compound I or pharmaceutically acceptable salts thereof, or solvates thereof is provided,




In another embodiment, the pharmaceutically acceptable salt is a p-toluenesulfonate.
In another embodiment, in p-toluenesulfonate of compound I, the molar ratio of compound I and p-toluenesulfonic acid is 1:1 or 2:1.
In another embodiment, the solvate is methanol or ethanol solvate of the p-toluenesulfonate of compound I.
In another embodiment, the polymorph is polymorph I of the 1/1 p-toluenesulfonate of compound I (1:1), wherein polymorph I has 1 to 3 characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 13.182±0.2°, 21.472±0.2° and 22.833±0.2°.
In another embodiment, polymorph I further has one or more characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 4.397±0.2°, 16.636±0.2°, 17.821±0.2°, 20.407±0.2° and 20.782±0.2°.
In another embodiment, polymorph I has characteristic peaks in X-ray powder diffraction as essentially shown in FIG. 1a. 
In another embodiment, polymorph I has a maximum peak of 231.5-237.7° C. in differential scanning calorimetry pattern.
In another embodiment, polymorph I has a differential scanning calorimetry pattern as essentially shown in FIG. 1b. 
In another embodiment, in polymorph I, the molar ratio of compound I and p-toluenesulfonic acid is 1:1.
In another embodiment, the polymorph is polymorph II of methanol solvate of the 1/1 p-toluenesulfonate of compound I (1:1:1), wherein polymorph II has 1 to 3 characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 21.014±0.2°, 18.333±0.2° and 25.301±0.2°.
In another embodiment, polymorph II further has one or more characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 8.405±0.2°, 15.906±0.2°, 19.477±0.2° and 24.744±0.2°.
In another embodiment, polymorph II has characteristic peaks in X-ray powder diffraction pattern as essentially shown in FIG. 2a. 
In another embodiment, polymorph II has maximum peaks of 193.5-197.0° C. and 228.6-236.4° C. in differential scanning calorimetry pattern.
In another embodiment, polymorph II of the methanol solvate has a differential scanning calorimetry pattern as essentially shown in FIG. 2b. 
In another embodiment, in polymorph II, the molar ratio of compound I, p-toluenesulfonic acid and methanol is 1:1:1.
In another embodiment, the polymorph is polymorph III of the 1/1 p-toluenesulfonate of compound I (1:1), wherein polymorph III has 1 or 2 characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 19.858±0.2° and 25.896±0.2°.
In another embodiment, polymorph III further has one or more characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 17.726±0.2°, 19.325±0.2° and 21.575±0.2°.
In another embodiment, polymorph III has characteristic peaks in X-ray powder diffraction pattern as essentially shown in FIG. 3a. 
In another embodiment, polymorph III has maximum peaks of 193.8-197.2° C. and 231.3-236.9° C. in differential scanning calorimetry pattern.
In another embodiment, polymorph III has a differential scanning calorimetry pattern as essentially shown in FIG. 3b. 
In another embodiment, in polymorph III, the molar ratio of compound I to p-toluenesulfonic acid is 1:1.
In another embodiment, the polymorph is polymorph IV of ethanol solvate of the 1/1 p-toluenesulfonate of compound I (1:1:1), wherein polymorph IV has 1 or 2 characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 20.961±0.2° and 18.277±0.2°.
In another embodiment, polymorph IV further has one or more characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 9.273±0.2°, 15.812±0.2°, 24.674±0.2°, 25.246±0.2° and 27.552±0.2°.
In another embodiment, polymorph IV has characteristic peaks in X-ray powder diffraction pattern as essentially shown in FIG. 4a. 
In another embodiment, polymorph IV has maximum peaks of 190.8-192.5° C. and 230.0-237.4° C. in differential scanning calorimetry pattern.
In another embodiment, polymorph IV has a differential scanning calorimetry pattern as essentially shown in FIG. 4b. 
In another embodiment, in polymorph IV, the molar ratio of compound I, p-toluenesulfonic acid and ethanol is 1:1:1.
In another embodiment, the polymorph is polymorph V of the 1/2 p-toluenesulfonate of compound I (2:1), wherein polymorph V has one or more characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 13.423±0.2°, 13.974±0.2°, 20.467±0.2°, 20.705±0.2°, 24.929±0.2° and 27.101±0.2°.
In another embodiment, polymorph V further has one or more characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 17.192±0.2°, 19.778±0.2°, 22.799±0.2°, 23.590±0.2° and 27.416±0.2°.
In another embodiment, polymorph V has characteristic peaks in X-ray powder diffraction pattern as essentially shown in FIG. 5a. 
In another embodiment, polymorph V has a maximum peak of 130-142.3° C. in differential scanning calorimetry pattern.
In another embodiment, polymorph V has a differential scanning calorimetry pattern as essentially shown in FIG. 5b. 
In another embodiment, in polymorph V, the molar ratio of compound I top-toluenesulfonic acid is 2:1.
In another embodiment, the polymorph is polymorph VI of compound I, wherein polymorph VI has one or more characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 23.818±0.2°, 24.236±0.2°, 26.382±0.2°, 26.817±0.2°, 24.929±0.2° and 27.101±0.2°.
In another embodiment, polymorph VI further has one or more characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 11.327±0.2°, 17.997±0.2°, 18.528±0.2° and 21.669±0.2°.
In another embodiment, polymorph VI has characteristic peaks in X-ray powder diffraction pattern as essentially shown in FIG. 6a. 
In another embodiment, polymorph VI has a maximum peak of 211.5-213.6° C. in differential scanning calorimetry pattern.
In another embodiment, polymorph VI has a differential scanning calorimetry pattern as essentially shown in FIG. 6b. 
In the second aspect, it provides a use of the polymorphs of the first aspect of the present invention in preparation of a pharmaceutical composition for inhibiting phosphokinase (such as raf kinase).
In another embodiment, the pharmaceutical composition is used for treating or preventing cancer.
In the third aspect, a pharmaceutical composition is provided, wherein the composition comprises:
(a) the polymorph of the first aspect of the present invention; and
(b) a pharmaceutically acceptable carrier.
In the fourth aspect, a method for preparing the polymorphs of the first aspect of the present invention is provided, comprising a step of: forming salt of compound I with an acid and crystallizing in an inert solvent, or recrystallizing compound I or pharmaceutically acceptable salts thereof or solvates thereof in an inert solvent, thereby obtaining the polymorphs of the first aspect of the present invention.
In another embodiment, the acid is p-toluenesulfonic acid.
In another embodiment, the method for preparing polymorph I comprises a step of: in an inert solvent, recrystallizing compound I with p-toluenesulfonic acid, thereby obtaining the polymorph I of the present invention.
In another embodiment, the method for preparing polymorph II comprises a step of: in methanol, recrystallizing the polymorph I obtained in the aforesaid step, thereby obtaining the polymorph II of the present invention.
In another embodiment, the method for preparing polymorph III comprises a step of: drying the polymorph II obtained in the aforesaid step for a period, thereby obtaining the polymorph III of the present invention.
In another embodiment, the method for preparing polymorph IV comprises a step of: in ethanol, recrystallizing the polymorph I obtained in the aforesaid step, thereby obtaining the polymorph IV of the present invention.
In another embodiment, the method for preparing polymorph V comprises a step of: drying the polymorph I obtained in the aforesaid step for a period, thereby obtaining the polymorph V of the present invention.
It should be understood that in the present invention, any of the technical features specifically described above and below (such as in the Examples) can be combined with each other, thereby constituting new or preferred technical solutions which will not redundantly be described one by one herein.



DESCRIPTION OF FIGURES
FIG. 1a shows an X-ray powder diffraction pattern of polymorph I of Example 1.
FIG. 1b shows a differential scanning calorimetry pattern of polymorph I of Example 1.
FIG. 1c shows a 1H NMR pattern of polymorph I of Example 1.
FIG. 2a shows an X-ray powder diffraction pattern of polymorph II of Example 2.
FIG. 2b shows a differential scanning calorimetry pattern of polymorph II of Example 2.
FIG. 2c shows a 1H NMR pattern of polymorph II of Example 2.
FIG. 3a shows an X-ray powder diffraction pattern of polymorph III of Example 3.
FIG. 3b shows a differential scanning calorimetry pattern of polymorph III of Example 3.
FIG. 3c shows a 1H NMR pattern of polymorph III of Example 3.
FIG. 4a shows an X-ray powder diffraction pattern of polymorph IV of Example 4.
FIG. 4b shows a differential scanning calorimetry pattern of polymorph IV of Example 4.
FIG. 4c shows a 1H NMR pattern of polymorph IV of Example 4.
FIG. 5a shows an X-ray powder diffraction pattern of polymorph V of Example 5.
FIG. 5b shows a differential scanning calorimetry pattern of polymorph V of Example 5.
FIG. 5c shows a 1H NMR pattern of polymorph V of Example 5.
FIG. 6a shows an X-ray powder diffraction pattern of polymorph VI of Example 6.
FIG. 6b shows a differential scanning calorimetry pattern of polymorph VI of Example 6.
FIG. 6c shows a 1H NMR pattern of polymorph VI of Example 6.
FIG. 7a shows an X-ray powder diffraction pattern of amorphous form of the p-toluenesulfonate of compound I.
FIG. 7b shows a differential scanning calorimetry pattern of amorphous form of the p-toluenesulfonate of compound I.
FIG. 7c shows a 1H NMR pattern of amorphous form of the p-toluenesulfonate of compound I.



DETAILED DESCRIPTION OF INVENTION
After intensive studies for a long time, the inventors have unexpectedly discovered various polymorphs of compound I or pharmaceutically acceptable salts thereof, or solvates thereof, which are highly pure, very stable, and suitable for preparing pharmaceutical compositions inhibiting phosphokinase (such as raf kinase). Therefore, they are more beneficial for treating diseases such as cancer. Moreover, the polymorphs of the present invention are not prone to floating in the manufacturing process (such as subpackaging) of a drug, easy for collection so that it is easy to avoid wasting and it is helpful to protect the health of operators. Based on this discovery, the inventors have completed the present invention.
As used herein, “Compound of Formula I (or compound I)” refers to 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)pico linamide as shown by Formula I.
p-Toluenesulfonate of 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)picolinamide
The p-toluenesulfonate of 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)picolinamide of the present invention comprises various forms of the p-toluenesulfonate of compound I.
Preferably, it is the 1/1 p-toluenesulfonate of 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)pico linamide, which refers to a salt wherein the ratio of compound I and p-toluenesulfonic acid is 1:1; or the 1/2 p-toluenesulfonate of 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)picolinamide, which refers to a salt wherein the ratio of compound I and p-toluenesulfonic acid is 2:1.
Polymorph
Solid exists in either an amorphous form or a crystal form. In the case of crystal form, the molecules orient in lattice sites of a 3D lattice. When a compound is crystallized from a solution or slurry, it can have various crystalline phases that have different arrangements and/or conformations of the molecules which called as “polymorphism”. Different polymorphs of a given substance may be different from each other in one or more physical properties, such as solubility and dissolution rate, true specific gravity, crystal form, accumulation mode, liquidity and/or solid state stability, and so on.
Crystallization
The production-scale crystallization can be achieved by operating a solution so as to exceed the solubility limit of a compound interested. This can be accomplished through a variety of methods, for example, dissolving a compound at a relatively high temperature, and then cooling the solution below a saturation limit, or reducing the liquid volume by boiling, atmospheric evaporation, vacuum drying or some other methods, or reducing the solubility of the interested compound by adding antisolvent or solvents with low solubility of the compound, or a mixture of such solvents. An alternative method is to reduce the solubility by adjusting the pH value. See Crystallization, Third Edition, J W Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294 for a detailed description of crystallization.
If formation of a salt and its crystallization are desired to occur simultaneously, and the solubility of salt is lower than the raw material in the reaction medium, then the salt can be crystallized directly by adding an appropriate acid or base. Similarly, in a medium in which the solubility of the desired final form is lower than that of reactant, the final product can directly crystallize when the synthetic reaction is completed.
Optimization of crystallization may include adding the crystal desired as a seed crystal in the crystallization medium. In addition, many crystallization methods use a combination of the above strategies. One way comprises: dissolving the interested compound in a solvent, then adding an antisolvent in an appropriate volume through a controlled mode, in order to make the system just below the saturation level. At this moment, the desired crystal seed may be added (the integrity of the seed is kept), then crystallization is achieved by cooling the system.
As used herein, the term “room temperature” generally refers to 4-30° C., preferably, 20±5° C.
Polymorph of the Present Invention
As used herein, the term “polymorphs of the present invention” comprises polymorphs of compound I or pharmaceutically acceptable salts thereof (such as the p-toluenesulfonate), or solvates thereof, and further comprises various polymorphs of a certain p-toluenesulfonate or solvates thereof.
The preferable polymorphs of the present invention include but are not limited to:
polymorph VI of compound I;
polymorph I or polymorph III of the 1/1 p-toluenesulfonate of compound I;
polymorph II of methanol solvate of the 1/1 p-toluenesulfonate of compound I or polymorph IV of ethanol solvate of the 1/1 p-toluenesulfonate of compound I; wherein, in polymorph II, the molar ratio of compound I, p-toluenesulfonic acid and methanol is 1:1:1; and in polymorph IV, the molar ratio of compound I, p-toluenesulfonic acid and ethanol is 1:1:1; and
polymorph V of the 1/2 p-toluenesulfonate of compound I.
Identification and Property of Polymorph
After preparing polymorphs of the p-toluenesulfonate of compound I, the property thereof is studied using various methods and instruments.
X-Ray Powder Diffraction
The method of X-ray powder diffraction determining crystal form is known in the field. For example, the pattern is obtained using copper radiation on X-ray powder diffractometer of Rigaku D/max 2550VB/PC, at a scanning rate of 2° per minute.
The polymorphs of the p-toluenesulfonate of compound I have a specific crystal form and specific characteristic peaks in X-ray powder diffraction pattern. The preferred embodiments include:
(1) Polymorph I
Polymorph I has one or more characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 13.182±0.2°, 21.472±0.2° and 22.833±0.2°. In another embodiment, polymorph I further has one or more characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 4.397±0.2°, 16.636±0.2°, 17.821±0.2°, 20.407±0.2° and 20.782±0.2°. In another embodiment, polymorph I has characteristic peaks in X-ray powder diffraction pattern as essentially shown in FIG. 1a. 
(2) Polymorph II
Polymorph II has one or more characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 21.014±0.2°, 18.333±0.2° and 25.301±0.2°. In another embodiment, polymorph II further has one or more characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 8.405±0.2°, 15.906±0.2°, 19.477±0.2° and 24.744±0.2°. In another embodiment, polymorph II has characteristic peaks in X-ray powder diffraction pattern as essentially shown in FIG. 2a. 
(3) Polymorph III
Polymorph III has 1 or 2 characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 19.858±0.2° and 25.896±0.2°. In another embodiment, polymorph III further has one or more characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 17.726±0.2°, 19.325±0.2° and 21.575±0.2°. In another embodiment, polymorph III has characteristic peaks in X-ray powder diffraction pattern as essentially shown in FIG. 3a. 
(4) Polymorph IV
Polymorph IV has one or more characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 20.961±0.2° and 18.277±0.2°. In another embodiment, polymorph IV further has one or more characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 9.273±0.2°, 15.812±0.2°, 24.674±0.2°, 25.246±0.2° and 27.552±0.2°. In another embodiment, polymorph IV has characteristic peaks in X-ray powder diffraction pattern as essentially shown in FIG. 4a. 
(5) Polymorph V
Polymorph V has one or more characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 13.423±0.2°, 13.974±0.2°, 20.467±0.2°, 20.705±0.2°, 24.929±0.2° and 27.101±0.2°. In another embodiment, polymorph V further has one or more characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 17.192±0.2°, 19.778±0.2°, 22.799±0.2°, 23.590±0.2° and 27.416±0.2°. In another embodiment, polymorph V has characteristic peaks in X-ray powder diffraction pattern as essentially shown in FIG. 5a. 
(6) Polymorph VI
Polymorph VI has one or more characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 23.818±0.2°, 24.236±0.2°, 26.382±0.2°, 26.817±0.2°, 24.929±0.2° and 27.101±0.2°. In another embodiment, polymorph VI further has one or more characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of 11.327±0.2°, 17.997±0.2°, 18.528±0.2° and 21.669±0.2°. In another embodiment, polymorph VI has characteristic peaks in X-ray powder diffraction pattern as essentially shown in FIG. 6a. 
Differential Scanning Calorimetry
Differential scanning calorimetry or DSC refers to a thermoanalytical technique in which the difference in the amount of energy required to increase the temperature of a sample and reference is measured as a function of temperature. Position, shape and number of peaks in DSC pattern are relevant to the properties of substance, so they can be used to identify a substance qualitatively. Generally, this method is use to detect phase transition temperature, glass transition temperature, reaction calorimetry and other parameters of a substance.
The method of DSC is known in the art. For example, differential scanning calorimeter of NETZSCH DSC 204 F1 can be used, at a heating rate of 10 degrees per minute, from 25° C. to 250° C., to obtain a DSC pattern of a crystal form.
The polymorphs of the p-toluenesulfonate of compound I have specific characteristic peaks in Differential Scanning calorimetry (DSC) pattern. Preferably, they are shown as follows:
(1) Polymorph I
Polymorph I has a maximum peak of 231.5-237.7° C. in DSC pattern. In another embodiment, polymorph I has a DSC pattern as essentially shown in FIG. 1b. 
(2) Polymorph II
Polymorph II has maximum peaks of 193.5-197.0° C. and 228.6-236.4° C. in DSC pattern. In another embodiment, polymorph II has a DSC pattern as essentially shown in FIG. 2b. 
(3) Polymorph III
Polymorph III has maximum peaks of 193.8-197.2° C. and 231.3-236.9° C. in DSC pattern. In another embodiment, polymorph III has a DSC pattern as essentially shown in FIG. 3b. 
(4) Polymorph IV
Polymorph IV has maximum peaks of 190.8-192.5° C. and 230.0-237.4° C. in DSC pattern. In another embodiment, polymorph IV has a DSC pattern as essentially shown in FIG. 4b. 
(5) Polymorph V
Polymorph V has a maximum peak of 130-142.3° C. in DSC pattern. In another embodiment, polymorph V has a DSC pattern as essentially shown in FIG. 5b. 
(6) Polymorph VI
Polymorph VI has a maximum peak of 211.5-213.6° C. in DSC pattern. In another embodiment, polymorph VI has a DSC pattern as essentially shown in FIG. 6b. 
Nuclear magnetic resonance (NMR) may further be used to assistantly determine the crystal structure. The detecting methods and instruments are known in the art, for example, one can use Bruker Avance III plus-400 MHz.
Active Ingredients
As used herein, the term “active ingredients” or “active compound” refers to the polymorphs of the present invention, i.e. polymorphs of compound I or pharmaceutically acceptable salts thereof (such as the p-toluenesulfonate), or solvates thereof.
Pharmaceutical Composition and the Administration Thereof
The polymorphs of the present invention possess outstanding activity of inhibiting phosphokinases, such as raf kinases. Therefore, the polymorphs of the present invention and the pharmaceutical composition comprising polymorphs of the present invention as a main active ingredient can be used for treating, preventing and alleviating diseases mediated by phosphokinases (e.g. raf kinase). Based on the prior art, the compounds of the invention can treat the following diseases: cancer, cardiovascular diseases, obesity, diabetes etc.
The pharmaceutical composition of the invention comprises the polymorph of the present invention in a safe and effective dosage range and pharmaceutically acceptable excipients or carriers.
Wherein, the term “safe and effective dosage” refers to the amount of the compounds (or the polymorphs) which is enough to improve the patient's condition without any serious side effect. Generally, the pharmaceutical composition contains 1-2000 mg polymorphs of the invention per dose, preferably, 10-200 mg polymorphs of the invention per dose. Preferably, “per dose” means one capsule or tablet.
“Pharmaceutically acceptable carrier” means one or more compatible solid or liquid fillers or gel materials, which are suitable for human, and must have sufficient purity and sufficiently low toxicity. “Compatibility” herein means that the components of the compositions can be blended with the compounds of the invention or with each other, and would not significantly reduce the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and the derivatives thereof (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), wetting agent (such as sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
There is no special limitation of administration mode for the polymorphs or pharmaceutical compositions of the present invention, and the representative administration mode includes (but is not limited to): oral, intratumoral, 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 ingredients are mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or CaHPO4, or mixed with any of the following components: (a) fillers or compatibilizer, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and arabic gum; (c) humectant, such as, glycerol; (d) disintegrating agents such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain composite silicates, and sodium carbonate; (e) dissolution-retarding agents, such as paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants such as talc, stearin calcium, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or the mixtures thereof. In capsules, tablets and pills, the dosage forms may also contain buffering agents.
The solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared by using coating and shell materials, such as enteric coatings and any other materials known in the art. They can contain a opaque agent. The release of the active compounds or compounds in the compositions can be released in a delayed mode in a given portion of the digestive tract. Examples of the embedding components include polymers and waxes. If necessary, the active compounds and one or more above excipients can form microcapsules.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredients, the liquid dosage forms may contain any conventional inert diluents known 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, dimethyl formamide, as well as oil, in particular, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or the combination thereof.
Besides these inert diluents, the composition may also contain additives such as wetting agents, emulsifiers, and suspending agent, sweetener, flavoring agents and perfume.
In addition to the active ingredients, the suspension may contain suspending agent, for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, methanol aluminum and agar, or the combination thereof.
The compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders which can be re-dissolved into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and any suitable mixtures thereof.
The dosage forms for topical administration of compounds of the invention include ointments, powders, patches, aerosol, and inhalants. The active ingredients are mixed with physiologically acceptable carriers and any preservatives, buffers, or propellant if necessary, under sterile conditions.
Polymorphs of the present invention can be administrated alone, or in combination with any other pharmaceutically acceptable compounds.
When the pharmaceutical compositions are used, a safe and effective amount of polymorph of the present invention is applied to a mammal (such as human) in need of, wherein the dose of administration is a pharmaceutically effective dose. For a person weighed 60 kg, the daily dose is usually 1-2000 mg, preferably 20-500 mg. Of course, the particular dose should also depend on various factors, such as the route of administration, patient healthy status, which are well within the skills of an experienced physician.
The main advantages of the present invention are:
1. a series of novel polymorphs of 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)picolinamide or salts thereof, or solvates thereof are provided, including polymorphs I to VI;
2. a use of various polymorphs in preparing a pharmaceutical composition useful for inhibiting phosphokinase (such as raf kinase) is provided.
The present invention will be further illustrated below with reference to the specific examples. It should be understood that these examples are only to illustrate the invention but not to limit the scope of the invention. The experimental methods with no specific conditions described in the following examples are generally performed under the conventional conditions, or according to the manufacture's instructions. Unless indicated otherwise, parts and percentage are calculated by weight.
Example 1: Polymorph I of the 1/1 p-toluenesulfonate of 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)picolinamide
50 g of methyl 4-chloro-2-picolinate was dissolved in 250 mL of tetrahydrofuran in a three-necked flask, then 31 g of deuterated methylamine hydrochloride and 80 g of anhydrous potassium carbonate were added respectively. After the mixture was stirred at 25° C. for 20 hours, 250 mL of water and 100 mL of methyl tert-butyl ether were added. The mixture was stirred and separated, and the aqueous phase was extracted with 100 mL of methyl tert-butyl ether. The organic phases were combined and dried, and the solvent was removed under reduced pressure to give 48 g of pale yellow liquid.
The pale yellow liquid was dissolved in 50 mL of dimethylsulfoxide, then 30 g of 4-aminophenol was added and 31 g of potassium t-butoxide was added in portions. The mixture was heated to 80° C. and stirred for 4 hours. 100 mL of hydrochloric acid was added dropwise, then the mixture was filtered and the filter cake was suspended in 150 mL of acetone. The suspension was stirred at 25° C. for 16 hours and filtered. The filter cake was dissolved in 100 mL of water, and extracted with 200 mL of ethyl acetate twice. The organic phase was dried, and the solvent was removed under reduced pressure to obtain 51 g of light brown solid.
The resultant light brown solid was dissolved in 50 mL of N,N-dimethylformamide. A solution of 4-chloro-3-trifluoromethylphenyl isocyanate (48 g) in ethyl acetate (50 mL) was added dropwise, and the mixture was stirred at 25° C. for 2 hours. Then 130 mL of water was added dropwise, and the mixture was stirred for 1 hour, filtered and dried to give 77 g of pale yellow solid, i.e., 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)pico linamide.
45 g of pale yellow solid was added into 450 mL of tetrahydrofuran, then 6.6 g of p-toluenesulfonic acid monohydrate was added. The mixture was heated to reflux until the solution was clear. After hot filtration, the filtrate was re-heated to reflux until the solution was clear, then a solution of p-toluenesulfonic acid monohydrate (16.1 g) in tetrahydrofuran (50 mL) at 70° C. was flowed into the above clear solution rapidly. Keep the temperature for 30 minutes, then stop heating and cool to 0° C. The mixture was filtered, and the filter cake was taken out and dried under vacuum for 24 hours at room temperature to constant weight to give 55.2 g of the title compound.
NMR data showed that the molar ratio of compound I and p-toluenesulfonic acid was 1:1.
1H NMR (DMSO-d6, 400 MHz): δ 2.30 (s, 3H), 7.15 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 7.23 (dd, J=2.8 Hz, 6 Hz, 1H), 7.52 (d, J=8 Hz, 2H), 7.55 (d, J=2.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 3H), 7.68 (dd, J=2.4 Hz, 9.2 Hz, 1H), 8.03 (br, 1H), 8.14 (d, J=2.4 Hz, 1H), 8.56 (d, J=6 Hz, 1H), 8.91 (br, 1H), 9.17 (br, 1H), 9.36 (br, 1H).
The X-ray powder diffraction pattern is shown in FIG. 1a, parameters of each peak are shown in Table 1, the differential scanning calorimetry pattern (DSC) is shown in FIG. 1b, and 1H NMR is shown in FIG. 1c.












TABLE 1










relative intensity



Peak No.
2θ(°)
Height
(I %)





















1
4.397
9535
59.02



2
10.643
1136
7.03



3
11.068
2874
17.79



4
11.608
1178
7.29



5
12.193
1266
7.84



6
12.791
2601
16.10



7
13.182
16155
100.00



8
14.759
5166
31.98



9
15.981
1603
9.92



10
16.636
7569
46.85



11
17.821
9542
59.07



12
18.764
4001
24.77



13
19.360
3516
21.76



14
20.030
5597
34.65



15
20.407
9135
56.55



16
20.782
8830
54.66



17
21.472
12236
75.74



18
22.076
1648
10.20



19
22.833
11201
69.33



20
23.345
3025
18.72



21
23.640
2644
16.37



22
24.472
3676
22.75



23
25.005
3472
21.49



24
25.355
2040
12.63



25
25.968
2673
16.55



26
26.578
2632
16.29



27
26.917
1622
10.04



28
27.292
1631
10.10



29
28.101
1845
11.42



30
28.535
2569
15.90



31
29.524
2219
13.74



32
29.837
1865
11.54



33
30.785
2058
12.74



34
31.084
1812
11.22



35
31.538
1674
10.36



36
31.974
1364
8.44



37
33.169
1275
7.89



38
33.863
1677
10.38



39
34.180
1580
9.78



40
35.695
1035
6.41



41
37.021
941
5.82



42
38.420
899
5.56



43
39.213
1352
8.37



44
41.124
1354
8.38










Example 2: Polymorph II of methanol solvate of the 1/1 p-toluenesulfonate of 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)pico linamide (The molar ratio of compound I, p-toluenesulfonic acid and methanol is 1:1:1)
10 g of polymorph I prepared in Example 1 was added into 100 g of methanol. The mixture was heated to reflux until the solution was clear, then a solution of p-toluenesulfonic acid monohydrate (6.1 g) in methanol (25 g) was added dropwise. The mixture was cooled to 30° C. naturally after it was clear, and then stirred for 1.5 hours, and filtered. The filter cake was taken out, dried under vacuum at room temperature to constant weight to give 12 g of white solid, which was sampled and characterized through 1H NMR, X-ray powder diffraction, DSC, etc., demonstrating that the title compound was obtained.
NMR data showed that the molar ratio of compound I, p-toluenesulfonic acid and methanol was 1:1:1.
1H NMR (DMSO-d6, 400 MHz): δ2.29 (s, 3H), 3.17 (s, 3H), 7.14 (d, J=8 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H), 7.24 (dd, J=2.4 Hz, 6 Hz, 1H), 7.52 (d, J=8 Hz, 2H), 7.57-7.69 (m, 5H), 8.13 (d, J=2 Hz, 1H), 8.38 (br, 1H), 8.56 (d, J=6.4 Hz, 1H), 8.95 (br, 1H), 9.20 (br, 1H), 9.39 (br, 1H).
The X-ray powder diffraction pattern is shown in FIG. 2a, parameters of each peak are shown in Table 2, the differential scanning calorimetry pattern (DSC) is shown in FIG. 2b, and 1H NMR is shown in FIG. 2c.












TABLE 2










relative intensity



Peak No.
2θ(°)
Height
(I %)





















1
7.996
3315
7.45



2
8.405
9975
22.41



3
9.370
5972
13.42



4
12.214
3052
6.86



5
13.085
2009
4.51



6
13.460
2179
4.90



7
15.906
10390
23.34



8
16.988
1079
2.42



9
17.777
1790
4.02



10
18.333
17222
38.70



11
19.020
4626
10.39



12
19.477
8049
18.08



13
20.281
1939
4.36



14
20.526
3444
7.74



15
21.014
44507
100.00



16
21.768
4833
10.86



17
22.477
5721
12.85



18
23.897
2109
4.74



19
24.744
10801
24.27



20
25.301
21550
48.42



21
25.730
3443
7.74



22
26.034
2925
6.57



23
26.957
6747
15.16



24
27.627
8140
18.29



25
28.416
2063
4.64



26
28.889
6042
13.58



27
29.165
3503
7.87



28
29.760
4274
9.60



29
30.270
1810
4.07



30
30.943
1966
4.42



31
31.494
2442
5.49



32
32.009
2651
5.96



33
33.017
2159
4.85



34
33.430
1923
4.32



35
34.181
1137
2.55



36
34.616
1512
3.40



37
37.281
1305
2.93



38
40.301
1345
3.02










Example 3: Polymorph III of the 1/1 p-toluenesulfonate of 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)picolinamide
2 g of polymorph II prepared in example 2 was dried in a vacuum oven at 85° C. for 20 hours to constant weight, which was sampled and determined through 1H NMR, X-ray powder diffraction, DSC, etc. The results demonstrated the title compound (1.85 g) was obtained.
NMR data showed that the molar ratio of compound I and p-toluenesulfonic acid was 1:1.
1H NMR (DMSO-d6, 400 MHz): δ2.29 (s, 3H), 3.17 (s, 3H), 7.13 (d, J=8 Hz, 2H), 7.19 (d, J=9.2 Hz, 2H), 7.22 (dd, J=2.4 Hz, 6 Hz, 1H), 7.50-7.53 (m, 3H), 7.60-7.69 (m, 4H), 8.13 (d, J=2.4 Hz, 1H), 8.38 (br, 1H), 8.55 (d, J=5.6 Hz, 1H), 8.90 (br, 1H), 9.15 (br, 1H), 9.35 (br, 1H), 9.63 (br, 1H).
The X-ray powder diffraction pattern is shown in FIG. 3a, parameters of each peak are shown in Table 3, the differential scanning calorimetry diagram (DSC) is shown in FIG. 3b, and 1H NMR is shown in FIG. 3c.












TABLE 3










relative intensity



Peak No.
2θ(°)
Height
(I %)





















1
7.676
723
5.55



2
8.546
1575
12.09



3
9.773
725
5.57



4
10.617
1144
8.78



5
11.982
2421
18.59



6
12.319
740
5.68



7
12.926
943
7.24



8
13.382
765
5.87



9
16.029
1892
14.53



10
17.193
2155
16.55



11
17.726
4749
36.47



12
18.792
1831
14.06



13
19.325
4336
33.29



14
19.858
13023
100.00



15
20.270
3203
24.59



16
20.826
2077
15.95



17
21.575
6037
46.36



18
22.483
1970
15.13



19
22.936
1186
9.11



20
23.370
1159
8.90



21
24.198
3194
24.53



22
24.834
1112
8.54



23
25.896
7377
56.65



24
26.864
1270
9.75



25
27.692
3058
23.48



26
28.149
1833
14.08



27
29.392
1911
14.67



28
29.787
2386
18.32



29
31.443
1557
11.96



30
32.175
1260
9.68



31
33.459
638
4.90



32
34.085
817
6.27



33
35.212
860
6.60



34
36.140
710
5.45



35
37.229
608
4.67



36
39.557
604
4.64



37
40.567
579
4.45



38
41.135
582
4.47



39
43.382
670
5.14



40
43.877
655
5.03










Example 4: polymorph IV of ethanol solvate of the 1/1 p-toluenesulfonate of 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)pico linamide (molar ratio of the compound of formula I, p-toluenesulfonic acid and ethanol is 1:1:1)
5 g of polymorph I prepared in example 1 was suspended in 20 ml of ethanol. The mixture was stirred at room temperature for 16 hours, and filtered. The filter cake out was taken out and dried in vacuo at room temperature for 20 hours to constant weight to give 4.8 g of pale yellow solid, which was sampled and determined through 1H NMR, X-ray powder diffraction, DSC, etc., demonstrating that the title compound was obtained.
NMR data showed that the molar ratio of compound I, p-toluenesulfonic acid and ethanol was 1:1:1.
1H NMR (DMSO-d6, 400 MHz): δ1.05 (t, J=6.8 Hz, 3H), 2.29 (s, 3H), 3.44 (q, J=7.2 Hz, 2H), 7.13 (d, J=7.6 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.22 (dd, J=2.8 Hz, 6 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.54 (d, J=2.8 Hz, 1H), 7.60-7.69 (m, 4H), 7.97 (br, 1H), 8.13 (d, J=2.4 Hz, 1H), 8.55 (d, J=6 Hz, 1H), 8.92 (br, 1H), 9.16 (br, 1H), 9.36 (br, 1H).
The X-ray powder diffraction pattern is shown in FIG. 4a, parameters of each peak are shown in Table 4, the differential scanning calorimetry pattern (DSC) is shown in FIG. 4b, and 1H NMR is shown in FIG. 4c.












TABLE 4










relative intensity



Peak No.
2θ(°)
Height
(I %)





















1
7.915
1966
17.64



2
8.386
1884
16.90



3
9.273
4236
38.00



4
9.534
786
7.05



5
11.186
741
6.65



6
11.976
2299
20.63



7
12.178
919
8.25



8
12.827
1362
12.22



9
13.417
711
6.38



10
15.812
3239
29.06



11
16.759
756
6.78



12
18.277
7399
66.38



13
18.832
2363
21.20



14
19.400
2656
23.83



15
19.954
813
7.29



16
20.414
1075
9.64



17
20.961
11146
100.00



18
21.456
2214
19.86



19
21.706
851
7.64



20
22.422
1986
17.82



21
23.786
1173
10.52



22
24.674
3954
35.47



23
25.246
4011
35.99



24
25.898
1159
10.40



25
26.353
1382
12.40



26
26.922
1896
17.01



27
27.552
3263
29.28



28
28.323
1168
10.48



29
28.818
2862
25.68



30
29.111
996
8.94



31
29.646
1226
11.00



32
30.378
920
8.25



33
30.872
1403
12.59



34
31.364
752
6.75



35
31.954
1151
10.33



36
32.924
1194
10.71



37
33.876
685
6.15



38
34.523
753
6.76



39
36.578
611
5.48



40
37.030
566
5.08



41
40.171
754
6.76



42
41.809
644
5.78



43
42.673
551
4.94



44
43.957
630
5.65










Example 5: Polymorph V of the 1/2 p-toluenesulfonate of 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)pico linamide
3 g of polymorph I prepared in example 1 was suspended in 50 ml of water. The mixture was stirred at room temperature for 24 hours, and filtered. The filter cake was taken out and dried in vacuo at room temperature for 48 hours, which was sampled and determined through 1H NMR, X-ray powder diffraction, DSC, etc., demonstrating that 1.2 g of title compound was obtained.
NMR data showed that the molar ratio of compound I and p-toluenesulfonic acid was 2:1.
1H NMR (DMSO-d6, 400 MHz): δ2.29 (s, 1.5H), 7.13 (d, J=8 Hz, 1H), 7.17-7.20 (m, 3H), 7.46 (d, J=2.4 Hz, 1H), 7.51 (d, J=8 Hz, 2H), 7.60-7.66 (m, 4H), 8.13 (d, J=2.4 Hz, 1H), 8.53 (d, J=6 Hz, 1H), 8.84 (br, 1H), 9.09 (br, 1H), 9.29 (br, 1H).
The X-ray powder diffraction pattern is shown in FIG. 5a, parameters of each peak are shown in Table 5, the differential scanning calorimetry diagram (DSC) is shown in FIG. 5b, and 1H NMR is shown in FIG. 5c.












TABLE 5










relative intensity



Peak No.
2θ(°)
Height
(I %)





















1
5.570
779
12.17



2
6.611
1161
18.13



3
8.010
959
14.98



4
9.017
3356
52.42



5
9.595
2872
44.86



6
9.869
2591
40.47



7
10.601
1063
16.60



8
10.914
1625
25.38



9
11.207
1266
19.78



10
11.891
814
12.71



11
12.749
1053
16.45



12
13.423
5460
85.29



13
13.974
6003
93.77



14
14.530
1645
25.70



15
15.019
1178
18.40



16
15.709
2621
40.94



17
16.108
1667
26.04



18
16.578
3549
55.44



19
16.757
3439
53.72



20
17.192
4282
66.89



21
18.320
3397
53.06



22
18.911
2251
35.16



23
19.283
2641
41.25



24
19.778
4064
63.48



25
20.467
5269
82.30



26
20.705
4945
77.24



27
21.003
1656
25.87



28
21.455
3511
54.84



29
22.000
1110
17.34



30
22.341
1770
27.65



31
22.799
3980
62.17



32
23.314
2515
39.28



33
23.590
4436
69.29



34
24.159
3616
56.48



35
24.929
6402
100.00



36
25.503
2651
41.41



37
25.721
3267
51.03



38
26.149
1873
29.26



39
27.101
5429
84.80



40
27.416
4202
65.64



41
28.265
2716
42.42



42
28.599
1432
22.37



43
29.133
1490
23.27



44
29.826
1737
27.13



45
30.282
1282
20.02



46
31.185
1473
23.01



47
31.625
1087
16.98



48
32.666
1453
22.70



49
33.551
1282
20.02



50
34.030
1512
23.62



51
34.781
1225
19.13



52
36.242
959
14.98



53
36.693
1297
20.26



54
37.308
965
15.07



55
37.722
933
14.57



56
38.155
974
15.21



57
38.845
1077
16.82



58
40.461
898
14.03



59
41.568
802
12.53



60
42.383
780
12.18



61
43.427
850
13.28










Example 6: polymorph VI of 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)picolinamide
50 g of methyl 4-chloro-2-picolinate was dissolved in 250 mL of tetrahydrofuran in three-necked flask, then 31 g of deuterated methylamine hydrochloride and 80 g of anhydrous potassium carbonate were added respectively. After the mixture was stirred at 25° C. for 20 hours, 250 mL of water and 100 mL of methyl tert-butyl ether were added, The mixture was stirred and separated, and the aqueous phase was extracted with 100 mL of methyl tert-butyl ether. The organic phases were combined and dried, the solvent was removed under reduced pressure to give 48 g of pale yellow liquid.
The pale yellow liquid was dissolved in 50 mL of dimethylsulfoxide, 30 g of 4-aminophenol was added and 31 g of potassium t-butoxide was added in portions. The mixture was heated to 80° C. and stirred for 4 hours. 100 mL of hydrochloric acid was added dropwise, then the mixture was filtered and the filter cake was suspended in 150 mL of acetone. The suspension was stirred at 25° C. for 16 hours, and filtered. The filter cake was dissolved in 100 mL of water, and extracted with 200 mL of ethyl acetate twice. The organic phase was dried, and the solvent was removed under reduced pressure to obtain 51 g of light brown solid.
The resultant light brown solid was dissolved in 50 mL of N,N-dimethylformamide. A solution of 4-chloro-3-trifluoromethylphenyl isocyanate (48 g) in ethyl acetate (50 mL) was added dropwise, and the mixture was stirred at 25° C. for 2 hours. Then 130 mL of water was added dropwise, and the mixture was stirred for 1 hour, filtered and dried in vacuo at 25° C. for 24 hours to give a pale yellow solid, which was sampled and determined through 1H NMR, X-ray powder diffraction, DSC, etc., demonstrating that the title compound (77 g) was obtained.
1H NMR (DMSO-d6, 400 MHz): δ7.15 (dd, J=2.8 Hz, 5.6 Hz, 1H), 7.17-7.19 (m, 2H), 7.40 (d, J=2.4 Hz, 1H), 7.59-7.69 (m, 4H), 8.13 (d, J=2.4 Hz, 1H), 8.51 (d, J=6 Hz, 1H), 8.75 (br, 1H), 8.90 (br, 1H), 9.22 (br, 1H).
The X-ray powder diffraction pattern is shown in FIG. 6a, parameters of each peak are shown in Table 6, the differential scanning calorimetry diagram (DSC) is shown in FIG. 6b, and 1H NMR is shown in FIG. 6c.












TABLE 6










relative intensity



Peak No.
2θ(°)
Height
(I %)





















1
6.549
1062
2.18



2
9.806
2156
4.42



3
11.327
5816
11.94



4
12.490
17961
36.86



5
13.105
2458
5.04



6
13.496
3135
6.43



7
14.484
5096
10.46



8
15.037
4170
8.56



9
15.551
3156
6.48



10
16.257
1228
2.52



11
17.033
2348
4.82



12
17.997
4940
10.14



13
18.528
5423
11.13



14
18.985
4093
8.40



15
19.711
5440
11.16



16
21.669
3610
7.41



17
21.925
7892
16.20



18
22.379
14496
29.75



19
22.834
27515
56.47



20
23.465
4326
8.88



21
23.818
2862
5.87



22
24.236
5232
10.74



23
24.686
48724
100.00



24
25.105
33185
68.11



25
25.555
7452
15.29



26
26.382
3451
7.08



27
26.817
4602
9.45



28
28.002
1827
3.75



29
28.418
1641
3.37



30
29.561
4191
8.60



31
30.293
3754
7.70



32
31.514
2316
4.75



33
32.543
1872
3.84



34
32.779
1838
3.77



35
34.990
2317
4.76



36
36.390
2058
4.22



37
37.849
2329
4.78



38
38.779
1223
2.51



39
40.021
2093
4.30



40
41.149
1194
2.45



41
41.913
1084
2.22



42
42.784
1718
3.53










Example 7: Amorphous form of the 1/1 p-toluenesulfonate of 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)pico linamide
0.5 g of polymorph I prepared in example 1 was suspended in 500 mL of ethanol. The mixture was heated under reflux until it was completely dissolved. The solvent was removed under reduced pressure at 80° C. using rotary evaporation, and the solid was dried in vacuo at 50° C. for 28 hours and milled to give a pale yellow powder, which was sampled and determined through 1H NMR, X-ray powder diffraction, DSC, etc., demonstrating that 0.41 g of the title compound was obtained.
NMR data showed that the molar ratio of compound I and p-toluenesulfonic acid was 1:1.
1H NMR (DMSO-d6, 400 MHz): δ2.30 (s, 3H), 7.15 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 7.23 (dd, J=2.8 Hz, 6 Hz, 1H), 7.52 (d, J=8 Hz, 2H), 7.55 (d, J=2.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 3H), 7.68 (dd, J=2.4 Hz, 9.2 Hz, 1H), 8.03 (br, 1H), 8.14 (d, J=2.4 Hz, 1H), 8.56 (d, J=6 Hz, 1H), 8.91 (br, 1H), 9.17 (br, 1H), 9.36 (br, 1H).
The X-ray powder diffraction pattern is shown in FIG. 7a, the differential scanning calorimetry pattern (DSC) is shown in FIG. 7b, and 1H NMR is shown in FIG. 7c. 
Example 8: Stability of polymorph I of the 1/1 p-toluenesulfonate of 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-2-(N-1′,1′,1′-trideutero-methyl)pico linamide
After an accelerated stability test (test condition: 40° C., 75% RH) for 1-6 months, the results showed that: crystal form of polymorph I was very stable; compared to polymorph I freshly prepared (0 Months), the purity of polymorph I was almost unchanged, always above 99%.
Example 9: Pharmaceutical Composition













Polymorph I of the 1/1 p-toluenesulfonate of
20 g


4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl)-ureido]-phenoxy}-


2-(N-1′,1′,1′-trideutero-methyl)picolinamide (Example 1)


Starch
140 g 


Microcrystalline cellulose
60 g









According to the conventional method, the above materials were mixed and encapsulated into ordinary gelatin capsule to give 1,000 capsules.
Example 10: Drug Hygroscopicity Test
The test was performed according to the guiding principles of drug hygroscopic test (Chinese Pharmacopoeia 2010 edition, Appendix XIX J).
1. Take 4 dry glass weighing bottles with a top (The outer diameter was 60 mm and height was 30 mm). On the day before the test, the bottles was placed in a glass dryer (A saturated ammonium sulfate solution was placed in the lower part thereof) in a thermostatic and humidistatic chamber at 25° C.±1° C. (hereinafter, “a humidistatic dryer at 25° C.±1° C.”). The weighing bottle and its top were placed separately without the top on the bottle. Cover the glass dryer closely.
2. After each empty weighing bottle together with its top were placed in a humidistatic dryer at 25° C.±1° C. for 24 hours, weigh a set (the weighing bottle+its top) as a unit precisely respectively, recorded as m1. Take a sample appropriately, tile it in a glass weighing bottle weighed at a sample thickness of about 1 mm, and cover the bottle. Precisely weigh the weighing bottle with its top and the sample, recorded as m2. Put 4 kinds of salts of free alkali compound I (ZJCM03) in 4 weighing bottles respectively. Then take off the top of the weighing bottles, and put the bottle and its top in the humidistatic dryer at 25° C.±1° C. for 24 hours.
3. After each sample were placed in a humidistatic dryer at 25° C.±1° C. for 24 hours, cover the weighing bottles with their tops respectively, and precisely weigh each weighing bottle with its top and the sample at this specific moment, recorded as m3.
4. Calculate the weight increase (%) of each sample according to the following equation.

the weight increase (%)=[(m3−m2)/(m2−m1)]×100%

It is defined as no or almost no hygroscopicity when the weight increase (%) is less than 0.2%.
According to the above steps, the hygroscopicity of the polymorphs of the present invention was tested. The results showed that the weight increase (%) of polymorph I=[(39.951−39.951)/(39.951−38.836)]×100%=0. The result showed that polymorph I had no hygroscopicity.
Repeat Example 8 and Example 10 except that polymorphs II, III, IV, V or VI was used instead of polymorph I. The results showed that each polymorph of the present invention was very stable, had no or almost no hygroscopicity.
Therefore, polymorphs of the present invention are very suitable to be used in pharmaceutical compositions. Moreover, the polymorphs of the present invention, which are not prone to floating in the manufacturing process (such as subpackaging) of a drug and are easy for collection so that it is easy to avoid wasting and it is helpful to protect the health of operators.
All literatures mentioned in the present application are incorporated by reference herein, as though individually incorporated by reference. Additionally, it should be understood that after reading the above teaching, many variations and modifications may be made by the skilled in the art, and these equivalents also fall within the scope as defined by the appended claims.

## Claims

1. A method of inhibiting phosphokinase in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a polymorph of a pharmaceutically acceptable p-toluensulfonate salt of compound I,



the polymorph being selected from the group consisting of polymorph I, III, and V of the p-toluenesulfonate of compound I, and polymorph IV of ethanol solvate of the p-toluenesulfonate of compound I,
wherein:
the polymorph I is polymorph I of the 1/1 p-toluenesulfonate of compound I, and the polymorph I comprises the following characteristic peaks in X-ray powder diffraction pattern:















Peak No.
2θ(°)



















1
4.397



2
10.643



3
11.068



4
11.608



5
12.193



6
12.791



7
13.182



8
14.759



9
15.981



10
16.636



11
17.821



12
18.764



13
19.360



14
20.030



15
20.407



16
20.782



17
21.472



18
22.076



19
22.833



20
23.345



21
23.640



22
24.472



23
25.005



24
25.355



25
25.968



26
26.578



27
26.917



28
27.292



29
28.101



30
28.535



31
29.524



32
29.837



33
30.785



34
31.084



35
31.538



36
31.974



37
33.169



38
33.863



39
34.180



40
35.695



41
37.021



42
38.420



43
39.213



44
41.124









and the polymorph I has a maximum peak of 237.7° C. in differential scanning calorimetry pattern;
the polymorph III is polymorph III of the 1/1 p-toluenesulfonate of compound I, and the polymorph III comprises the following characteristic peaks in X-ray powder diffraction pattern: 19.858±0.2°, 25.896±0.2°, 17.726±0.2°, 19.325±0.2° and 21.575±0.2°;
the polymorph V is polymorph V of the 1/2 p-toluenesulfonate of compound I, and the polymorph V comprises the following characteristic peaks in X-ray powder diffraction pattern: 13.423±0.2°, 13.974±0.2°, 20.467±0.2°, 20.705±0.2°, 24.929±0.2°, 27.101±0.2°, 17.192±0.2°, 19.778±0.2°, 22.799±0.2°, 23.590±0.2° and 27.416±0.2°; and
the polymorph IV is polymorph IV of ethanol solvate of the 1/1 p-toluenesulfonate of compound I (1:1:1), and the polymorph IV comprises the following characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of: 20.961±0.2°, 18.277±0.2°, 9.273±0.2°, 15.812±0.2°, 24.674±0.2°, 25.246±0.2° and 27.552±0.2°.

2. The method of claim 1, wherein the subject has a cancer.

3. The method of claim 1, wherein the subject is a human.

4. The method of claim 1, wherein the polymorph is polymorph I of the 1/1 p-toluenesulfonate of compound I, and the polymorph I has a DSC pattern as shown in FIG. 1b.

5. A method for preparing a pharmaceutical composition for inhibiting phosphokinase, comprising:
(a) mixing a polymorph of a pharmaceutically acceptable p-toluensulfonate salt of compound I with a pharmaceutically acceptable excipient, thereby forming the pharmaceutical composition,




the polymorph being selected from the group consisting of polymorph I, III, and V of the p-toluenesulfonate of compound I, and polymorph IV of ethanol solvate of the p-toluenesulfonate of compound I,
wherein:
the polymorph I is polymorph I of the 1/1 p-toluenesulfonate of compound I, and the polymorph I comprises the following characteristic peaks in X-ray powder diffraction pattern:















Peak No.
2θ(°)



















1
4.397



2
10.643



3
11.068



4
11.608



5
12.193



6
12.791



7
13.182



8
14.759



9
15.981



10
16.636



11
17.821



12
18.764



13
19.360



14
20.030



15
20.407



16
20.782



17
21.472



18
22.076



19
22.833



20
23.345



21
23.640



22
24.472



23
25.005



24
25.355



25
25.968



26
26.578



27
26.917



28
27.292



29
28.101



30
28.535



31
29.524



32
29.837



33
30.785



34
31.084



35
31.538



36
31.974



37
33.169



38
33.863



39
34.180



40
35.695



41
37.021



42
38.420



43
39.213



44
41.124









and the polymorph I has a maximum peak of 237.7° C. in differential scanning calorimetry pattern;
the polymorph III is polymorph III of the 1/1 p-toluenesulfonate of compound I, and the polymorph III comprises the following characteristic peaks in X-ray powder diffraction pattern: 19.858±0.2°, 25.896±0.2°, 17.726±0.2°, 19.325±0.2° and 21.575±0.2°;
the polymorph V is polymorph V of the 1/2 p-toluenesulfonate of compound I, and the polymorph V comprises the following characteristic peaks in X-ray powder diffraction pattern: 13.423±0.2°, 13.974±0.2°, 20.467±0.2°, 20.705±0.2°, 24.929±0.2°, 27.101±0.2°, 17.192±0.2°, 19.778±0.2°, 22.799±0.2°, 23.590±0.2° and 27.416±0.2°; and
the polymorph IV is polymorph IV of ethanol solvate of the 1/1 p-toluenesulfonate of compound I (1:1:1), and the polymorph IV comprises the following characteristic peaks in X-ray powder diffraction pattern selected from the group consisting of: 20.961±0.2°, 18.277±0.2°, 9.273±0.2°, 15.812±0.2°, 24.674±0.2°, 25.246±0.2° and 27.552±0.2°.

6. The method of claim 5, wherein the phosphokinase is raf kinase.

7. The method of claim 5, wherein the polymorph is polymorph I of the 1/1 p-toluenesulfonate of compound I, and the polymorph I has a DSC pattern as shown in FIG. 1b.