CN106316963B - Polymorphs of a morpholino phenylaminopyrimidine compound or salt thereof - Google Patents
Polymorphs of a morpholino phenylaminopyrimidine compound or salt thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention relates to polymorphs of a morpholinophenylamino pyrimidine compound or a salt thereof, and more particularly to polymorphs of N- (cyanomethyl) -4- (2- (4- (morpholinophenylamino) pyrimidin-4-yl) benzamide, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a polymorph of a morpholine phenylamino pyrimidine compound or a salt thereof, and more particularly relates to a polymorph of N- (cyanomethyl) -4- (2- (4- (morpholine phenylamino) pyrimidin-4-yl) benzamide or a pharmaceutically acceptable salt thereof.
Background
N- (cyanomethyl) -4- (2- (4- (morpholinophenylamino) pyrimidin-4-yl) benzamide (N- (cyanomethyl) -4- (2- ((4-morpholino) phenyl) amino) pyrimidin-4-yl) benzamide) having the structure shown in formula I:
formula I
The compound of formula I has the molecular formula C23H22N6O2The molecular weight is 414.46, the compound is an inhibitor of non-receptor tyrosine kinase such as JAK kinase, and is suitable for preparing medicaments for treating/preventing cancer, myeloproliferative diseases, inflammation and other related diseases.
Because different crystal forms and salt forms of the medicine can influence the dissolution and absorption of the medicine in vivo, the clinical curative effect and the safety of the medicine can be influenced to a certain extent, and especially, the influence of the crystal forms is larger for some indissolvable oral solid or semisolid preparations. No study has been made on polymorphic forms of the compound of formula I and no polymorphic form of the compound of formula I has been developed.
Therefore, it is essential to develop polymorphs of the compound of formula I.
Disclosure of Invention
It is an object of the present invention to provide a polymorph of a compound of formula I or a pharmaceutically acceptable salt thereof, or a solvate thereof.
In a first aspect, the present invention provides a polymorph of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof,
formula I.
In another preferred embodiment, the pharmaceutically acceptable salt is a hydrochloride salt.
In another preferred embodiment, in the hydrochloride salt of the compound of formula I, the molar ratio of the compound of formula I to hydrochloric acid is about 1:1 or 1: 2.
in another preferred embodiment, the solvate is a monohydrate of the hydrochloride salt of the compound shown in the formula I.
In another preferred embodiment, the polymorph is polymorph I of the hydrochloride of the compound shown in formula I, wherein the polymorph I has 3 or more than 3X-ray powder diffraction characteristic peaks selected from the following group: 5.427 + -0.2 deg., 9.968 + -0.2 deg., 13.437 + -0.2 deg., 14.726 + -0.2 deg., 23.921 + -0.2 deg., 25.068 + -0.2 deg., 26.470 + -0.2 deg. and 29.452 + -0.2 deg..
In another preferred embodiment, the polymorph I has X-ray powder diffraction characteristic peaks selected from the group consisting of: 8.824 + -0.2 deg., 15.574 + -0.2 deg., 17.173 + -0.2 deg., 19.247 + -0.2 deg., 20.784 + -0.2 deg., 27.063 + -0.2 deg. and 30.220 + -0.2 deg..
In another preferred embodiment, said polymorph I has X-ray powder diffraction characteristic peaks substantially as shown in figure 1 a.
In another preferred embodiment, the differential scanning calorimetry pattern of polymorph I has a maximum peak at 219.7 ℃ ± 2 ℃ (or ± 1 ℃, or ± 0.5 ℃).
In another preferred embodiment, the polymorph I has a Differential Scanning Calorimetry (DSC) pattern substantially as shown in figure 1 b.
In another preferred embodiment, the polymorph I has a molar ratio of the compound of formula I to hydrochloric acid of about 1: 2.
in another preferred embodiment, the polymorph is polymorph II of a hydrochloride solvate of the compound shown in formula I, wherein the polymorph II has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 17.310 + -0.2 deg., 18.553 + -0.2 deg., 19.227 + -0.2 deg., 22.643 + -0.2 deg., 23.964 + -0.2 deg. and 29.511 + -0.2 deg..
In another preferred embodiment, said polymorph II has X-ray powder diffraction characteristic peaks selected from the group consisting of: 15.278 + -0.2 deg., 16.699 + -0.2 deg., 24.617 + -0.2 deg., 25.600 + -0.2 deg., 27.119 + -0.2 deg. and 30.282 + -0.2 deg..
In another preferred embodiment, said polymorph II has X-ray powder diffraction characteristic peaks substantially as shown in figure 2 a.
In another preferred embodiment, the differential scanning calorimetry pattern of polymorph II has maximum peaks at 140.87 ℃. + -. 2 ℃ (or. + -. 1 ℃, or. + -. 0.5 ℃), 182.2 ℃. + -. 2 ℃ (or. + -. 1 ℃, or. + -. 0.5 ℃) and 234.34 ℃. + -. 2 ℃ (or. + -. 1 ℃, or. + -. 0.5 ℃).
In another preferred embodiment, the polymorph II has a Differential Scanning Calorimetry (DSC) pattern substantially as shown in figure 2 b.
In another preferred embodiment, the polymorph II has a molar ratio of the compound of formula I, hydrochloric acid and water of about 1: 2: 1.
in another preferred embodiment, the polymorph II is a monohydrate of the dihydrochloride salt of the compound of formula I.
In another preferred embodiment, the polymorph is polymorph III of the hydrochloride salt of the compound shown in formula I, wherein the polymorph III has 3 or more than 3X-ray powder diffraction characteristic peaks selected from the following group: 15.217 + -0.2 deg., 18.847 + -0.2 deg., 20.724 + -0.2 deg., 26.372 + -0.2 deg., and 28.107 + -0.2 deg..
In another preferred embodiment, said polymorph III further has 1 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 4.404 + -0.2 deg., 13.362 + -0.2 deg., 16.225 + -0.2 deg., 16.976 + -0.2 deg., 20.055 + -0.2 deg., 22.956 + -0.2 deg., 25.996 + -0.2 deg. and 31.783 + -0.2 deg..
In another preferred embodiment, said polymorph III has an X-ray powder diffraction pattern substantially as shown in figure 3 a.
In another preferred embodiment, the differential scanning calorimetry pattern of polymorph III has a maximum peak at 231.1 ℃ ± 2 ℃ (or ± 1 ℃, or ± 0.5 ℃).
In another preferred embodiment, the polymorph III has a Differential Scanning Calorimetry (DSC) pattern substantially as shown in figure 3 b.
In another preferred embodiment, the polymorph III has a molar ratio of the compound of formula I to hydrochloric acid of about 1: 1.
in another preferred embodiment, the polymorph is polymorph IV of the hydrochloride salt of the compound shown in formula I, wherein the polymorph IV has 3 or more than 3X-ray powder diffraction characteristic peaks selected from the following group: 4.422 + -0.2 deg., 12.474 + -0.2 deg., 14.429 + -0.2 deg., 17.627 + -0.2 deg., 19.501 + -0.2 deg., 23.213 + -0.2 deg., 23.803 + -0.2 deg. and 24.794 + -0.2 deg..
In another preferred embodiment, said polymorph IV further has 1 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 12.949 +/-0.2 degrees, 13.778 +/-0.2 degrees, 16.600 +/-0.2 degrees, 17.018 +/-0.2 degrees, 20.625 +/-0.2 degrees, 21.003 +/-0.2 degrees, 21.891 +/-0.2 degrees, 24.377 +/-0.2 degrees, 28.718 +/-0.2 degrees, 29.550 +/-0.2 degrees and 31.739 +/-0.2 degrees.
In another preferred embodiment, said polymorph IV has an X-ray powder diffraction pattern substantially as shown in figure 4 a.
In another preferred embodiment, the differential scanning calorimetry pattern of polymorph IV has a maximum peak at 245.24 ℃ ± 2 ℃ (or ± 1 ℃, or ± 0.5 ℃).
In another preferred embodiment, the polymorph IV has a Differential Scanning Calorimetry (DSC) pattern substantially as shown in figure 4 b.
In another preferred embodiment, the polymorph IV has a molar ratio of the compound of formula I to hydrochloric acid of about 1: 1.
in another preferred embodiment, the polymorph is polymorph V of the compound of formula I, wherein polymorph V has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 4.342 +/-0.2 degrees, 12.753 +/-0.2 degrees, 18.161 +/-0.2 degrees and 23.193 +/-0.2 degrees.
In another preferred embodiment, said polymorph V further has 1 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 5.981 + -0.2 deg., 9.495 + -0.2 deg., 14.014 + -0.2 deg., 19.680 + -0.2 deg., 21.280 + -0.2 deg., 24.319 + -0.2 deg., 25.326 + -0.2 deg. and 30.143 + -0.2 deg..
In another preferred embodiment, said polymorph V has an X-ray powder diffraction pattern substantially as shown in figure 5 a.
In another preferred embodiment, the differential scanning calorimetry pattern of polymorph V has a maximum peak at 256.79 ℃ ± 2 ℃ (or ± 1 ℃, or ± 0.5 ℃).
In another preferred embodiment, the polymorph V has a Differential Scanning Calorimetry (DSC) pattern substantially as shown in figure 5 b.
In a second aspect, the present invention provides the use of a polymorph according to the first aspect of the invention for the preparation of a pharmaceutical composition of a non-receptor tyrosine kinase, such as a JAK kinase.
In another preferred embodiment, the pharmaceutical composition is used for the treatment and prevention of cancer, myeloproliferative and inflammatory diseases.
In a third aspect, the present invention provides 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, the present invention provides a process for the preparation of a polymorph according to the first aspect of the present invention, comprising the steps of: crystallizing the compound of formula I and an acid as a salt in an inert solvent, or recrystallizing the compound of formula I or a pharmaceutically acceptable salt thereof, or a solvate thereof in an inert solvent to obtain the polymorph of the first aspect of the present invention.
In another preferred embodiment, the recrystallization is carried out with or without seeding.
In another preferred embodiment, the acid is hydrochloric acid.
In another preferred embodiment, the process for the preparation of the polymorph I comprises the steps of: crystallizing the compound of formula I and hydrochloric acid as salts in an inert solvent to obtain polymorph I according to the present invention.
In another preferred embodiment, the inert solvent is selected from the group consisting of: ethanol, methanol, isopropanol, acetic acid, formic acid, or combinations thereof.
In another preferred embodiment, the process for the preparation of the polymorph I comprises the steps of: salt-forming crystallization of the compound of formula I and hydrochloric acid in ethanol and/or methanol gives the polymorph I according to the invention.
In another preferred embodiment, the process for the preparation of the polymorph I comprises the steps of: the compound of the formula I and hydrochloric acid are subjected to salt-forming crystallization in a mixed solvent of acetic acid and ethanol, so that the polymorphic substance I is obtained.
In another preferred embodiment, the molar ratio of the compound of formula I to hydrochloric acid is about 1:2 to about 1: 5.
In another preferred embodiment, the volume ratio of the ethanol to the methanol is 1: 50-50: 1.
In another preferred embodiment, the volume ratio of the acetic acid to the ethanol is 1: 5-5: 1, preferably 1: 2-2: 1.
In another preferred embodiment, the process for preparing the polymorph II comprises the steps of: crystallizing the compound of formula I in a mixed solvent of dimethyl sulfoxide and ethanol or a mixed solvent of dimethyl sulfoxide and acetone to obtain the polymorphic substance II.
In another preferred embodiment, the volume ratio of the dimethyl sulfoxide to the ethanol is 1: 5-5: 1; the volume ratio of the dimethyl sulfoxide to the acetone is 1: 5-5: 1.
In another preferred embodiment, the process for preparing the polymorph II comprises the steps of: the polymorph I thus obtained is left in an environment of high humidity (e.g. 90% humidity) for a certain period of time, thus obtaining the polymorph II according to the invention.
In another preferred embodiment, the process for preparing the polymorph III comprises the steps of: crystallizing the compound of formula I and hydrochloric acid in a mixed solvent of N-methyl pyrrolidone and ethanol to obtain the polymorphic substance III.
In another preferred embodiment, the volume ratio of the N-methylpyrrolidone to the ethanol is 3:1 to 1:3, preferably 2:1 to 1:2, and more preferably 1: 1.
In another preferred embodiment, the process for preparing the polymorph III comprises the steps of: the polymorph II obtained is crystallized in methanol to give the polymorph III according to the invention.
In another preferred embodiment, the process for the preparation of polymorph IV comprises the steps of: the polymorph I obtained is recrystallized in water or aqueous hydrochloric acid to give the polymorph IV according to the invention.
In another preferred embodiment, the process for the preparation of polymorph V comprises the steps of: recrystallizing the compound shown in the formula I in a mixed solvent of acetic acid and water or a mixed solvent of dimethyl sulfoxide and water to obtain the polymorphic substance V.
In another preferred example, the volume ratio of the acetic acid to the water is 1: 3-3: 1; the volume ratio of the dimethyl sulfoxide to water is 1: 3-3: 1.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
Figure 1a shows the X-ray powder diffraction pattern of polymorph I.
Figure 1b shows a differential scanning calorimetry trace of polymorph I.
FIG. 1c shows polymorph I1HNMR map.
Figure 2a shows the X-ray powder diffraction pattern of polymorph II.
Figure 2b shows a differential scanning calorimetry trace of polymorph II.
FIG. 2c shows polymorph II1H NMR chart.
Figure 3a shows the X-ray powder diffraction pattern of polymorph III.
Figure 3b shows a differential scanning calorimetry trace of polymorph III.
FIG. 3c shows polymorph III1HNMR map.
Figure 4a shows the X-ray powder diffraction pattern of polymorph IV.
Figure 4b shows a differential scanning calorimetry trace of polymorph IV.
FIG. 4c shows polymorph IV1HNMR map.
Figure 5a shows the X-ray powder diffraction pattern of polymorph V.
Figure 5b shows a differential scanning calorimetry trace of polymorph V.
FIG. 5c shows polymorph V1HNMR map.
In each of the above figures, onset represents an initial value (initial value), and peak represents a peak (peak value).
Detailed Description
The present inventors have unexpectedly found, through long and intensive studies, a plurality of polymorphic forms of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which polymorphic forms have better pharmaceutical bioavailability, are highly pure and stable, and are suitable for preparing pharmaceutical compositions for inhibiting non-receptor tyrosine kinases (such as JAK kinases), thereby being more beneficial to the treatment of diseases such as cancer, myeloproliferative diseases and inflammation. In addition, the polymorphic substance is not easy to raise, collect and waste in the process of manufacturing split-charging and other medicines, and is beneficial to protecting the health of operators. On this basis, the inventors have completed the present invention.
As used herein, "compound of formula I" refers to N- (cyanomethyl) -4- (2- (4- (morpholinophenylamino) pyrimidin-4-yl) benzamide having the structural formula shown in formula I.
As used herein, "inert solvent" refers to methanol, ethanol, isopropanol, dimethyl sulfoxide, N-methylpyrrolidone, N, N-dimethylformamide, acetone, acetonitrile, acetic acid, formic acid, N-hexane, N-heptane, toluene, tetrahydrofuran, ethyl acetate, 1, 4-dioxane, methyl tert-butyl ether, water, or a mixture of the above solvents.
N- (cyanomethyl) -4- (2- (4- (morpholinophenylamino) pyrimidin-4-yl) benzamide hydrochloride
The N- (cyanomethyl) -4- (2- (4- (morpholinophenylamino) pyrimidin-4-yl) benzamide hydrochloride salt described herein includes various hydrochloride salt forms of the compound of formula I.
Preferably, N- (cyanomethyl) -4- (2- (4- (morpholinophenylamino) pyrimidin-4-yl) benzamide dihydrochloride, which refers to a salt of the compound of formula I with hydrochloric acid in a molar ratio of 1:2, or
N- (cyanomethyl) -4- (2- (4- (morpholinophenylamino) pyrimidin-4-yl) benzamide dihydrochloride monohydrate, which is a salt of the compound of formula I with hydrochloric acid and water in a molar ratio of 1: 2: 1.
N- (cyanomethyl) -4- (2- (4- (morpholinophenylamino) pyrimidin-4-yl) benzamide monohydrochloride, which refers to a salt of the compound of formula I with hydrochloric acid in a molar ratio of 1: 1.
Polymorphic substance
The solid is present either in amorphous or crystalline form. In the case of crystalline forms, the molecules are positioned within three-dimensional lattice sites. When a compound crystallizes from a solution or slurry, it can crystallize in different spatial lattice arrangements (this property is known as "polymorphism"), forming crystals with different crystalline forms, each of which is known as a "polymorph". Different polymorphs of a given substance may differ from each other in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystal form, packing pattern, flowability, and/or solid state stability.
Crystallization of
Production scale crystallization can be accomplished by manipulating the solution such that the solubility limit of the compound of interest is exceeded. This can be accomplished by a variety of methods, for example, dissolving the compound at relatively high temperatures and then cooling the solution below the saturation limit. Or by boiling, atmospheric evaporation, vacuum drying, or by some other method to reduce the liquid volume. The solubility of the compound of interest may be reduced by adding an anti-solvent or a solvent in which the compound has low solubility or a mixture of such solvents. Another alternative is to adjust the pH to reduce solubility. For a detailed description of the Crystallization see crystallation, third edition, J W Mullins, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.
If salt formation is desired to occur simultaneously with crystallization, addition of an appropriate acid or base may result in direct crystallization of the desired salt if the salt is less soluble in the reaction medium than the starting material. Also, in media where the final desired form is less soluble than the reactants, completion of the synthesis reaction can result in direct crystallization of the final product.
Optimization of crystallization may include seeding the crystallization medium with crystals of the desired form. In addition, many crystallization methods use a combination of the above strategies. One example is to dissolve the compound of interest in a solvent at elevated temperature, followed by the addition of an appropriate volume of anti-solvent in a controlled manner so that the system is just below the saturation level. At this point, seeds of the desired form may be added (and the integrity of the seeds maintained) and the system cooled to complete crystallization.
As used herein, the term "room temperature" generally means 4-30 deg.C, preferably 20. + -. 5 deg.C.
Polymorphs of the invention
As used herein, the term "polymorph of the invention" includes polymorphs of a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt), or various solvates thereof, and also includes different polymorphs of the same hydrochloride salt or solvate.
Preferred polymorphs of the present invention include (but are not limited to):
polymorph I of the dihydrochloride salt of the compound of formula I;
polymorph II of the dihydrochloride monohydrate of the compound of formula I;
polymorphs III and IV of the monohydrochloride salt of the compound of formula I;
polymorph V of the compound of formula I;
wherein, in the polymorphic substance I, the molar ratio of the compound shown in the formula I to the hydrochloric acid is 1: 2; in the polymorphic form II, the molar ratio of the compound of formula I, hydrochloric acid and water is 1: 2: 1; in said polymorphs III and IV, the molar ratio of the compound of formula I to hydrochloric acid is 1: 1.
identification and Properties of polymorphs
After preparing the polymorphic form of the compound of formula I, the present inventors investigated its properties in various ways and instruments as follows.
Powder X-ray diffraction
Methods for determining X-ray powder diffraction of crystalline forms are known in the art. The spectra were acquired using a copper radiation target, for example, using a Rigaku D/max 2550VB/PC model X-ray powder diffractometer, at a scanning speed of 2 ° per minute.
The polymorphic substance of the compound shown as the formula I has specific crystal form morphology and specific characteristic peaks in an X-ray powder diffraction (XRPD) pattern. The following are preferred:
(1) polymorph I
The polymorph I has 3 or more than 3X-ray powder diffraction characteristic peaks selected from the following group: 5.427 + -0.2 deg., 9.968 + -0.2 deg., 13.437 + -0.2 deg., 14.726 + -0.2 deg., 23.921 + -0.2 deg., 25.068 + -0.2 deg., 26.470 + -0.2 deg. and 29.452 + -0.2 deg.. In another preferred embodiment, the polymorph I has X-ray powder diffraction characteristic peaks selected from the group consisting of: 8.824 + -0.2 deg., 15.574 + -0.2 deg., 17.173 + -0.2 deg., 19.247 + -0.2 deg., 20.784 + -0.2 deg., 27.063 + -0.2 deg. and 30.220 + -0.2 deg.. In another preferred embodiment, the polymorph I has an X-ray powder diffraction pattern substantially as shown in figure 1 a.
(2) Polymorph II
The polymorph II has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 17.310 + -0.2 deg., 18.553 + -0.2 deg., 19.227 + -0.2 deg., 22.643 + -0.2 deg., 23.964 + -0.2 deg. and 29.511 + -0.2 deg.. In another preferred embodiment, said polymorph II has X-ray powder diffraction characteristic peaks selected from the group consisting of: 15.278 + -0.2 deg., 16.699 + -0.2 deg., 24.617 + -0.2 deg., 25.600 + -0.2 deg., 27.119 + -0.2 deg. and 30.282 + -0.2 deg.. In another preferred embodiment, said polymorph II has an X-ray powder diffraction pattern substantially as shown in figure 2 a.
(3) Polymorph III
The polymorph III has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 15.217 + -0.2 deg., 18.847 + -0.2 deg., 20.724 + -0.2 deg., 26.372 + -0.2 deg., and 28.107 + -0.2 deg.. In another preferred embodiment, said polymorph III further has 1 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 4.404 + -0.2 deg., 13.362 + -0.2 deg., 16.225 + -0.2 deg., 16.976 + -0.2 deg., 20.055 + -0.2 deg., 22.956 + -0.2 deg., 25.996 + -0.2 deg. and 31.783 + -0.2 deg.. In another preferred embodiment, said polymorph III has an X-ray powder diffraction pattern substantially as shown in figure 3 a.
(4) Polymorph IV
The polymorph IV has 3 or more X-ray powder diffraction characteristic peaks selected from the following group: 4.422 + -0.2 deg., 12.474 + -0.2 deg., 14.429 + -0.2 deg., 17.627 + -0.2 deg., 19.501 + -0.2 deg., 23.213 + -0.2 deg., 23.803 + -0.2 deg. and 24.794 + -0.2 deg.. In another preferred embodiment, said polymorph IV further has 1 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 12.949 +/-0.2 degrees, 13.778 +/-0.2 degrees, 16.600 +/-0.2 degrees, 17.018 +/-0.2 degrees, 20.625 +/-0.2 degrees, 21.003 +/-0.2 degrees, 21.891 +/-0.2 degrees, 24.377 +/-0.2 degrees, 28.718 +/-0.2 degrees, 29.550 +/-0.2 degrees and 31.739 +/-0.2 degrees. In another preferred embodiment, said polymorph IV has an X-ray powder diffraction pattern substantially as shown in figure 4 a.
(5) Polymorph V
The polymorph V has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 4.342 +/-0.2 degrees, 12.753 +/-0.2 degrees, 18.161 +/-0.2 degrees and 23.193 +/-0.2 degrees. In another preferred embodiment, said polymorph V further has 1 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 5.981 + -0.2 deg., 9.495 + -0.2 deg., 14.014 + -0.2 deg., 19.680 + -0.2 deg., 21.280 + -0.2 deg., 24.319 + -0.2 deg., 25.326 + -0.2 deg. and 30.143 + -0.2 deg.. In another preferred embodiment, said polymorph V has an X-ray powder diffraction pattern substantially as shown in figure 5 a.
Differential scanning calorimetry analysis
Also known as differential thermal scanning analysis (DSC), is a technique for measuring the relationship between the energy difference between a measured substance and a reference substance and the temperature during heating. The position, shape and number of peaks on a DSC spectrum are related to the nature of the substance and can be used qualitatively to identify the substance. The method is commonly used in the field to detect various parameters such as phase transition temperature, glass transition temperature, reaction heat and the like of a substance.
DSC measurement methods are known in the art. For example, a DSC scan of the crystalline form can be obtained using a NETZSCH DSC 204F 1 differential scanning calorimeter with a temperature ramp rate of 10 ℃ per minute from 25 ℃ to 300 ℃.
The polymorphic substance of the compound shown as the formula I has specific characteristic peaks in a Differential Scanning Calorimetry (DSC) chart.
(1) Polymorph I
The differential scanning calorimetry pattern of the polymorphic form I has a maximum peak at 219.7 ℃ + -2 ℃ (or + -1 ℃, or + -0.5 ℃).
In another preferred embodiment, the polymorph I has a Differential Scanning Calorimetry (DSC) pattern substantially as shown in figure 1 b.
(2) Polymorph II
The differential scanning calorimetry pattern of polymorph II has maximum peaks at 140.87 ℃ + -2 ℃ (or + -1 ℃, or + -0.5 ℃), 182.2 ℃ + -2 ℃ (or + -1 ℃, or + -0.5 ℃) and 234.34 ℃ + -2 ℃ (or + -1 ℃, or + -0.5 ℃).
In another preferred embodiment, the polymorph II has a Differential Scanning Calorimetry (DSC) pattern substantially as shown in figure 2 b.
(3) Polymorph III
The differential scanning calorimetry pattern of polymorph III has a maximum peak at 231.1 ℃ + -2 ℃ (or + -1 ℃, or + -0.5 ℃).
In another preferred embodiment, the polymorph III has a differential scanning calorimetry pattern substantially as shown in figure 3 b.
(4) Polymorph IV
The differential scanning calorimetry pattern of the polymorphic form IV has a maximum peak at 245.24 ℃ + -2 ℃ (or + -1 ℃, or + -0.5 ℃).
In another preferred embodiment, the polymorph IV has a differential scanning calorimetry pattern substantially as shown in figure 4 b.
(5) Polymorph V
The differential scanning calorimetry pattern of polymorph V has a maximum peak at 256.79 ℃ + -2 ℃ (or + -1 ℃, or + -0.5 ℃).
In another preferred embodiment, the polymorph V has a differential scanning calorimetry pattern substantially as shown in figure 5 b.
Nuclear Magnetic Resonance (NMR) can also be used to aid in the determination of the crystalline structure, the determination 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 present invention, i.e., a polymorph of a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., a hydrochloride salt thereof), or a solvate thereof.
Pharmaceutical compositions and methods of administration
Since the polymorph of the present invention has excellent inhibitory activity against non-receptor tyrosine kinases such as JAK kinases, the polymorph of the present invention and a pharmaceutical composition containing the polymorph of the present invention as a main active ingredient can be used for the treatment, prevention and alleviation of diseases mediated by non-receptor tyrosine kinases such as JAK kinases. According to the prior art, the polymorphs of the present invention are useful for the treatment of the following diseases: cancer, myeloproliferative and inflammatory disorders, and the like.
The pharmaceutical compositions of the present invention comprise a polymorph of the present invention in a safe and effective amount range, together with pharmaceutically acceptable excipients or carriers.
Wherein "safe and effective amount" means: the amount of the compound (or polymorph) is sufficient to significantly ameliorate the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of the polymorph/dose of the invention, more preferably, 10-200mg of the polymorph/dose of the invention. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of being combined with the active ingredients of the present invention and with each other without significantly diminishing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the polymorph or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are 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 ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following: (a) fillers or extenders, for example, microcrystalline cellulose, starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, crospovidone, croscarmellose sodium; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be delayed in a certain portion of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active ingredient may also be in microencapsulated form with one or more of the above excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredients, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these materials, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the polymorphic forms of the invention for topical administration include ointments, powders, patches, sprays 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 present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When the pharmaceutical composition is used, a safe and effective amount of the polymorphic substance of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1-2000mg, preferably 10-500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The main advantages of the invention include:
1. a series of novel polymorphs of N- (cyanomethyl) -4- (2- (4- (morpholinophenylamino) pyrimidin-4-yl) benzamide or a pharmaceutically acceptable salt thereof, or a solvate thereof are provided.
2. Also provided are uses of the polymorphs to prepare pharmaceutical compositions for inhibiting non-receptor tyrosine kinases, such as JAK kinases, for treating diseases such as cancer, myeloproliferative and inflammatory disorders.
The invention is further illustrated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight. Unless otherwise indicated, all amounts including quantities, percentages, fractions, and ratios are understood to be modified by the word "about," and amounts are not intended to represent significant figures.
EXAMPLE 1 preparation of polymorph I of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride
Taking 1.0g N- (cyanomethyl) -4- (2- (4- (morpholine) phenylamino) pyrimidin-4-yl) benzamide, adding 40ml of anhydrous methanol, stirring at room temperature, dripping 4.8ml of newly prepared hydrochloric acid ethanol solution (the concentration of hydrogen chloride is 40mg/ml) at room temperature, filtering after dripping, continuously stirring the filtrate at room temperature for 2h, separating out a solid, filtering, leaching with the anhydrous methanol, and drying the solid at 55 +/-5 ℃ for 6h under high vacuum to obtain a yellow solid.
Sampling channel1Detection by H NMR, X-ray powder diffraction, DSC, etc. confirmed the title crystalline compound, weighing 870mg, yield: 74 percent.
1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),9.56(t,J＝4.0Hz,1H),8.65(d,J＝4.0Hz,1H),8.30(d,J＝8.0Hz,2H),8.09(d,J＝8.0Hz,2H),7.98(d,J＝8.0Hz,2H),7.81(d,J＝8.0Hz,2H),7.58(d,J＝8.0Hz,1H),4.36(d,J＝4.0Hz,2H),4.10(s,4H),3.57(s,4H)。
Elemental analysis: c: 56.33%, H: 5.33%, N: 17.05 percent.
The X-ray powder diffraction pattern is shown in figure 1a, the parameters of each peak are shown in table 1, the Differential Scanning Calorimetry (DSC) pattern is shown in figure 1b,1the spectrum of H NMR is shown in 1 c.
TABLE 1
| Peak number | 2θ(°) | Peak height | Relative intensity (I%) | Peak number | 2θ(°) | Peak height | Relative intensity (I%) |
| 1 | 5.427 | 1232 | 36.7 | 19 | 25.068 | 3354 | 100.0 |
| 2 | 7.601 | 394 | 11.7 | 20 | 26.470 | 1964 | 58.6 |
| 3 | 8.824 | 587 | 17.5 | 21 | 27.063 | 1182 | 35.2 |
| 4 | 9.968 | 1914 | 57.1 | 22 | 28.129 | 737 | 22.0 |
| 5 | 12.757 | 463 | 13.8 | 23 | 28.938 | 565 | 16.8 |
| 6 | 13.437 | 985 | 29.4 | 24 | 29.452 | 1250 | 37.3 |
| 7 | 14.726 | 1604 | 47.8 | 25 | 30.220 | 1099 | 32.8 |
| 8 | 15.574 | 944 | 28.1 | 26 | 31.105 | 463 | 13.8 |
| 9 | 16.364 | 790 | 23.6 | 27 | 32.073 | 423 | 12.6 |
| 10 | 17.173 | 1036 | 30.9 | 28 | 32.572 | 422 | 12.6 |
| 11 | 17.943 | 862 | 25.7 | 29 | 34.171 | 448 | 13.4 |
| 12 | 18.569 | 537 | 16.0 | 30 | 36.258 | 375 | 11.2 |
| 13 | 19.247 | 1068 | 31.8 | 31 | 37.680 | 353 | 10.5 |
| 14 | 19.945 | 368 | 11.0 | 32 | 39.027 | 396 | 11.8 |
| 15 | 20.784 | 734 | 21.9 | 33 | 39.578 | 377 | 11.2 |
| 16 | 22.309 | 511 | 15.2 | 34 | 40.796 | 369 | 11.0 |
| 17 | 22.916 | 732 | 21.8 | 35 | 41.769 | 353 | 10.5 |
| 18 | 23.921 | 1635 | 48.7 |
EXAMPLE 2 preparation of polymorph I of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride
Taking 500mg of N- (cyanomethyl) -4- (2- (4- (morpholine) phenylamino) pyrimidine-4-yl) benzamide, adding 10ml of anhydrous methanol, stirring at room temperature, dripping 2.6ml of newly prepared methanol hydrochloride solution (the concentration of hydrogen chloride is 40mg/ml) at room temperature, adding crystal seeds of the polymorphic substance I after dripping, stirring overnight, filtering, washing with anhydrous methanol, and drying the solid at 55 +/-5 ℃ for 6h under high vacuum to obtain a yellow solid, namely the title crystalline compound, weighing 488mg, and obtaining the yield: 81 percent. The X-ray powder diffraction pattern is the same as that of figure 1 a.
EXAMPLE 3 preparation of polymorph I of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride
Taking 1.0g N- (cyanomethyl) -4- (2- (4- (morpholine) phenylamino) pyrimidin-4-yl) benzamide, adding 10ml of absolute ethyl alcohol, stirring at room temperature, dripping 4.8ml of newly prepared hydrochloric acid ethanol solution (the concentration of hydrogen chloride is 40mg/ml) at room temperature, continuing stirring for 2h after dripping, filtering, washing with absolute ethyl alcohol, and drying the solid at 55 +/-5 ℃ in high vacuum for 6h to obtain a yellow solid, namely the title crystal form compound, weighing 1.11g, and obtaining the yield: 91 percent. The X-ray powder diffraction pattern is the same as that of figure 1 a.
EXAMPLE 4 preparation of polymorph I of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride
Taking 500mg of N- (cyanomethyl) -4- (2- (4- (morpholine) phenylamino) pyrimidin-4-yl) benzamide, adding 2.0ml of glacial acetic acid, stirring at room temperature until the mixture is clear, dripping 2.6ml of newly prepared hydrochloric acid ethanol solution (the concentration of hydrogen chloride is 40mg/ml) at room temperature, continuously stirring for 2h after dripping is finished, separating out a solid, filtering, washing with absolute ethyl alcohol, and drying the solid at 55 +/-5 ℃ for 6h under high vacuum to obtain a yellow solid, namely the title crystal form compound, weighing 543mg, and obtaining the yield: 91 percent. The X-ray powder diffraction pattern is the same as that of figure 1 a.
EXAMPLE 5 preparation of polymorph II of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride monohydrate
Taking 500mg of N- (cyanomethyl)) -4- (2- (4- (morpholine) phenylamino) pyrimidin-4-yl) benzamide, adding 1.0ml of N-methylpyrrolidone, stirring at room temperature until the mixture is clear, dripping 2.6ml of newly prepared hydrochloric acid ethanol solution (the concentration of hydrogen chloride is 40mg/ml) at room temperature, continuing stirring at room temperature for 2 hours after dripping, filtering, quickly leaching with absolute ethyl alcohol, and drying at 55 +/-5 ℃ for 6 hours under high vacuum to obtain a yellow solid.
Sampling channel1Detection by H NMR, X-ray powder diffraction, DSC, etc. confirmed the title compound as the crystalline form, weighing 579mg, yield: 93 percent。
1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),9.57(t,J＝8.0Hz,1H),8.65(d,J＝4.0Hz,1H),8.30(d,J＝8.0Hz,2H),8.09(d,J＝8.0Hz,2H),7.98(d,J＝8.0Hz,2H),7.82(d,J＝8.0Hz,2H),7.58(d,J＝8.0Hz,1H),6.78(brs,2H)，4.36(d,J＝8.0Hz,2H),4.11(s,4H),3.58(s,4H)。
Elemental analysis: c: 55.06%, H: 5.52%, N: 16.34 percent;
the X-ray powder diffraction pattern is shown in figure 2a, the parameters of each peak are shown in table 2, the Differential Scanning Calorimetry (DSC) pattern is shown in figure 2b,1the spectrum of H NMR is shown in 2 c.
TABLE 2
EXAMPLE 6 preparation of polymorph II of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride monohydrate
Adding a compound N- (cyanomethyl)) -4- (2- (4- (morpholine) phenylamino) pyrimidin-4-yl) benzamide (87.0g,0.21mol) and dimethyl sulfoxide (260ml) into a four-neck flask, stirring at room temperature until the mixture is clear, slowly dripping 400ml (the concentration of hydrogen chloride is 40mg/ml) of a newly prepared hydrochloric acid ethanol solution into the mixture at room temperature until the mixture is completely dripped in about 30min, continuously stirring for 3h after the dripping is completed, filtering, quickly leaching a filter cake by using absolute ethyl alcohol, and drying at 55 +/-5 ℃ for 6h under high vacuum to obtain a yellow solid, namely the title crystal form compound, weighing 86.1g, and obtaining the yield: 83 percent. The X-ray powder diffraction pattern is the same as that of fig. 2 a.
EXAMPLE 7 preparation of polymorph II of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride monohydrate
Adding N- (cyanomethyl)) -4- (2- (4- (morpholine) phenylamino) pyrimidin-4-yl) benzamide (4.0g,9.6mmol) and dimethyl sulfoxide (14.0ml) into a four-neck flask, stirring at room temperature until the mixture is clear, adding 1.7ml of 37% concentrated hydrochloric acid into the mixture at one time, uniformly stirring, adding acetone (16ml), clarifying the mixed solution, continuously stirring at room temperature for 3 hours, filtering, washing a filter cake with acetone, and drying at 45 +/-5 ℃ for 3 hours under high vacuum to obtain a yellow solid, namely the title crystalline compound, weighing 3.3g of the title crystalline compound, and obtaining the yield: 68 percent. The X-ray powder diffraction pattern is the same as that of fig. 2 a.
EXAMPLE 8 preparation of polymorph II of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride monohydrate
Adding N- (cyanomethyl)) -4- (2- (4- (morpholine) phenylamino) pyrimidin-4-yl) benzamide (1.0g) and dimethyl sulfoxide (2.5ml) into a four-neck flask, stirring at room temperature until the mixture is clear, slowly dropping 5ml (the concentration of hydrogen chloride is 40mg/ml) of a newly prepared hydrochloric acid methanol solution into the mixture at room temperature, continuously stirring for 3 hours after the dropping is finished, filtering, quickly leaching a filter cake by using anhydrous methanol, and drying at 55 +/-5 ℃ for 6 hours under high vacuum to obtain a yellow solid, namely the title crystal form compound, wherein the weight is 0.91g, and the yield is as follows: 75 percent. The X-ray powder diffraction pattern is the same as that of fig. 2 a.
EXAMPLE 9 preparation of polymorph II of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride monohydrate
A 230.0 sample of 230.0g N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride (polymorph I) was ground in a mortar and placed in an environment with humidity greater than 90% for 4 days to give the title compound as a yellow solid, weighing 237g, yield: 99 percent. The X-ray powder diffraction pattern is essentially the same as in figure 2 a.
EXAMPLE 10 polymorph III of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide hydrochloride
Suspending 1.0g N- (cyanomethyl) -4- (2- (4- (morpholine) phenylamino) pyrimidin-4-yl) benzamide in a mixed solution of N-methylpyrrolidone and absolute ethyl alcohol (10ml, v: v ═ 1:1), dripping 2.6ml (the concentration of hydrogen chloride is 40mg/ml) of a newly prepared ethanol solution of hydrochloric acid at room temperature, continuing stirring for 3h after dripping, filtering, washing with absolute ethyl alcohol, and drying the solid at 55 +/-5 ℃ for 6h under high vacuum to obtain an off-white solid.
Sampling channel1Detection by H NMR, X-ray powder diffraction, DSC, etc. confirmed the title compound as crystalline form, weighing 836mg, yield: 70 percent.
1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),9.45(t,J＝4.0Hz,1H),8.62(d,J＝8.0Hz,1H),8.30(d,J＝8.0Hz,2H),8.06(d,J＝8.0Hz,2H),7.89(d,J＝8.0Hz,2H),7.54-7.53(m,3H),4.36(d,J＝8.0Hz,2H),3.98(s,4H),3.43(s,4H)。
Elemental analysis: 61.15 percent of C, 5.54 percent of H and 18.28 percent of N.
The X-ray powder diffraction pattern is shown in FIG. 3a, the parameters of each peak are shown in Table 3, the Differential Scanning Calorimetry (DSC) pattern is shown in FIG. 3b,1the spectrum of H NMR is shown in 3 c.
TABLE 3
| Peak number | 2θ(°) | Peak height | Relative intensity (I%) | Peak number | 2θ(°) | Peak height | Relative intensity (I%) |
| 1 | 4.404 | 743 | 11.0 | 17 | 23.964 | 1222 | 18.0 |
| 2 | 9.238 | 742 | 11.0 | 18 | 25.342 | 1065 | 15.7 |
| 3 | 10.282 | 578 | 8.5 | 19 | 25.996 | 1696 | 25.0 |
| 4 | 12.546 | 730 | 10.8 | 20 | 26.372 | 2559 | 37.8 |
| 5 | 13.362 | 1384 | 20.4 | 21 | 27.084 | 1010 | 14.9 |
| 6 | 14.035 | 742 | 11.0 | 22 | 28.107 | 2131 | 31.5 |
| 7 | 15.217 | 4747 | 70.1 | 23 | 29.012 | 743 | 11.0 |
| 8 | 16.225 | 1831 | 27.0 | 24 | 30.241 | 872 | 12.9 |
| 9 | 16.976 | 1575 | 23.3 | 25 | 31.227 | 846 | 12.5 |
| 10 | 17.982 | 1018 | 15.0 | 26 | 31.783 | 958 | 14.1 |
| 11 | 18.847 | 1974 | 29.1 | 27 | 32.846 | 806 | 11.9 |
| 12 | 20.055 | 1845 | 27.2 | 28 | 34.660 | 607 | 9.0 |
| 13 | 20.724 | 6774 | 100.0 | 29 | 37.390 | 486 | 7.2 |
| 14 | 21.751 | 1092 | 16.1 | 30 | 38.136 | 473 | 7.0 |
| 15 | 22.188 | 1167 | 17.2 | 31 | 41.885 | 469 | 6.9 |
| 16 | 22.956 | 1961 | 28.9 |
EXAMPLE 11 polymorph III of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide hydrochloride
150mg of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride monohydrate (polymorph II) was suspended in 6ml of anhydrous methanol, stirred at room temperature for 24h, filtered, washed with anhydrous methanol, and the solid was dried at 55 + -5 ℃ under high vacuum for 6h to give the title crystalline compound as an off-white solid, which was weighed 130mg, yield: 93 percent. The X-ray powder diffraction pattern is the same as that of fig. 3 a.
EXAMPLE 12 polymorph IV of (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide hydrochloride
Taking 500mg of N- (cyanomethyl) -4- (2- (4- (morpholine) phenylamino) pyrimidine-4-yl) benzamide, dripping 2.3ml (the concentration of hydrogen chloride is 40mg/ml) of newly prepared ethanol solution of hydrochloric acid, supplementing 2ml of purified water, stirring for 3h at room temperature, filtering, washing with tetrahydrofuran, drying for 3h at high vacuum and room temperature to obtain a white solid, and sampling to obtain a white solid1Detection by H NMR, X-ray powder diffraction, DSC, etc. confirmed the title crystalline compound, weighing 425mg, yield: 78 percent.
1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),9.47(t,J＝4.0Hz,1H),8.62(d,J＝4.0Hz,1H),8.30(d,J＝8.0Hz,2H),8.07(d,J＝8.0Hz,2H),7.90(d,J＝8.0Hz,2H),7.55-7.54(m,3H),4.37(d,J＝4.0Hz,2H),4.00(s,4H),3.45(s,4H)。
Elemental analysis: 61.33 percent of C, 5.36 percent of H and 18.54 percent of N.
The X-ray powder diffraction pattern is shown in FIG. 4a, the parameters of each peak are shown in Table 4, the Differential Scanning Calorimetry (DSC) pattern is shown in FIG. 4b,1the spectrum of H NMR is shown in 4 c.
TABLE 4
| Peak number | 2θ(°) | Peak height | Relative intensity (I%) | Peak number | 2θ(°) | Peak height | Relative intensity (I%) |
| 1 | 4.422 | 1816 | 60.9 | 20 | 26.517 | 961 | 32.2 |
| 2 | 8.921 | 416 | 13.9 | 21 | 27.082 | 688 | 23.1 |
| 3 | 12.474 | 2117 | 71.0 | 22 | 27.596 | 789 | 26.4 |
| 4 | 12.949 | 793 | 26.6 | 23 | 28.130 | 681 | 22.8 |
| 5 | 13.778 | 650 | 21.8 | 24 | 28.718 | 790 | 26.5 |
| 6 | 14.429 | 2623 | 87.9 | 25 | 29.550 | 998 | 33.5 |
| 7 | 16.600 | 710 | 23.8 | 26 | 30.180 | 1045 | 35.0 |
| 8 | 17.018 | 973 | 32.6 | 27 | 30.768 | 658 | 22.1 |
| 9 | 17.627 | 2633 | 88.3 | 28 | 31.739 | 660 | 22.1 |
| 10 | 19.501 | 2983 | 100.0 | 29 | 33.458 | 1328 | 44.5 |
| 11 | 20.625 | 662 | 22.2 | 30 | 35.018 | 591 | 19.8 |
| 12 | 21.003 | 644 | 21.6 | 31 | 35.747 | 636 | 21.3 |
| 13 | 21.891 | 625 | 21.0 | 32 | 37.419 | 569 | 19.1 |
| 14 | 22.404 | 1214 | 40.7 | 33 | 39.102 | 409 | 13.7 |
| 15 | 23.213 | 2023 | 67.8 | 34 | 39.775 | 391 | 13.1 |
| 16 | 23.803 | 1852 | 62.1 | 35 | 40.208 | 488 | 16.4 |
| 17 | 24.377 | 804 | 27.0 | 36 | 41.174 | 462 | 15.5 |
| 18 | 24.794 | 1797 | 60.2 | 37 | 41.869 | 536 | 18.0 |
| 19 | 25.797 | 961 | 32.2 | 38 | 42.756 | 526 | 17.6 |
EXAMPLE 13 polymorph IV of (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide hydrochloride
Taking a 300mg N- (cyanomethyl) -4- (2- (4- (morpholine) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride monohydrate (polymorphic II) sample, adding 12.0ml of purified water, stirring the sample to be clear, stirring the sample at room temperature for 3 hours, separating out a white solid, filtering the white solid, washing the white solid with tetrahydrofuran, and drying the white solid at room temperature for 3 hours to obtain the white solid, namely the title crystalline compound, weighing 185mg, and obtaining the yield: and 69 percent. The X-ray powder diffraction pattern is the same as that of fig. 4 a.
Example 14 polymorph IV of cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide hydrochloride
Taking 1.0g N- (cyanomethyl) -4- (2- (4- (morpholine) phenylamino) pyrimidin-4-yl) benzamide, adding 5.0ml of 1M hydrochloric acid, stirring at room temperature overnight, separating out a white solid, filtering, washing with tetrahydrofuran, and drying at room temperature in high vacuum for 3 hours to obtain the white solid, namely the title crystal form compound, wherein the weight is 785mg, and the yield is as follows: 72 percent. The X-ray powder diffraction pattern is the same as that of fig. 4 a.
EXAMPLE 15 polymorph V of (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide
N- (cyanomethyl) -4- (2- (4- (morpholine) phenylamino) pyrimidin-4-yl) benzamide (80.0g) and acetic acid (270mL) were added to the reaction flask and dissolved with stirring. The solution was slowly added dropwise to purified water (540mL), stirred at room temperature for 4 hours, filtered, and the filter cake was rinsed with purified water (0.2L x 3) and drained as much as possible. Drying the solid at 70 deg.C under high vacuum for 6 hr to obtain yellow solid, sampling, and collecting filtrate1H NMR, X-ray powder diffraction, DSC and other detection prove that the crystal form compound is the title crystal form compound, 58.0g is weighed, and the yield is as follows: 72.5 percent.
1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),9.36(t,J＝4.0Hz,1H),8.55(d,J＝4.0Hz,1H),8.28(d,J＝8.0Hz,2H),8.04(d,J＝8.0Hz,2H),7.68(d,J＝8.0Hz,2H),7.41(d,J＝8.0Hz,1H),6.94(d,J＝8.0Hz,2H),4.37(d,J＝8.0Hz,2H),3.75(t,J＝4.0Hz,4H),3.05(t,J＝4.0Hz,4H)。
Elemental analysis: c66.50% H5.18% N20.01%
The X-ray powder diffraction pattern is shown in FIG. 5a, the parameters of each peak are shown in Table 5, the Differential Scanning Calorimetry (DSC) pattern is shown in FIG. 5b,1the spectrum of H NMR is shown in 5 c.
TABLE 5
| Peak number | 2θ(°) | Peak height | Relative intensity (I%) | Peak number | 2θ(°) | Peak height | Relative intensity (I%) |
| 1 | 4.342 | 5318 | 45.8 | 17 | 19.680 | 2987 | 25.7 |
| 2 | 5.981 | 2484 | 21.4 | 18 | 20.407 | 1063 | 9.2 |
| 3 | 6.373 | 649 | 5.6 | 19 | 21.280 | 1951 | 16.8 |
| 4 | 9.495 | 1991 | 17.1 | 20 | 21.729 | 1478 | 12.7 |
| 5 | 10.046 | 1072 | 9.2 | 21 | 23.193 | 5429 | 46.7 |
| 6 | 12.042 | 997 | 8.6 | 22 | 23.748 | 1496 | 12.9 |
| 7 | 12.753 | 11617 | 100.0 | 23 | 24.319 | 3051 | 26.3 |
| 8 | 13.462 | 1041 | 9.0 | 24 | 24.826 | 1626 | 14.0 |
| 9 | 14.014 | 2597 | 22.4 | 25 | 25.326 | 2885 | 24.8 |
| 10 | 14.309 | 1580 | 13.6 | 26 | 26.057 | 1868 | 16.1 |
| 11 | 15.476 | 604 | 5.2 | 27 | 27.387 | 922 | 7.9 |
| 12 | 16.362 | 1233 | 10.6 | 28 | 28.125 | 1306 | 11.2 |
| 13 | 17.705 | 1723 | 14.8 | 29 | 29.352 | 894 | 7.7 |
| 14 | 18.161 | 5373 | 46.3 | 30 | 30.143 | 1340 | 11.5 |
| 15 | 18.575 | 1462 | 12.6 | 31 | 38.238 | 501 | 4.3 |
| 16 | 19.285 | 1308 | 11.3 |
EXAMPLE 16 polymorph V of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide
N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride (23.0g) was added to dimethyl sulfoxide (105ml), and the mixture was stirred at room temperature to be clear; slowly dropping the mixed solution into saturated sodium bicarbonate solution (1.1L) under stirring to precipitate solid, and continuously stirring for 4 h; filtering, washing the solid with purified water (100ml x 3), and drying at about 65 ℃ under high vacuum for 8h to obtain 18.8g of yellow solid, namely the title crystal form compound, with the yield: 96 percent. The X-ray powder diffraction pattern is the same as that of fig. 5 a.
EXAMPLE 17 stability of polymorph I of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride
After 6 months of accelerated testing (test conditions 40. + -. 2 ℃ C., 75%. + -. 5% RH), the results show that: the polymorphic form I is very stable, and compared with the newly prepared (month 0) polymorphic form I, the purity of the polymorphic form I is basically unchanged and is always over 99 percent, and no obvious degradation impurity is seen.
EXAMPLE 18 stability of polymorph II of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride monohydrate
After 6 months of accelerated testing (test conditions 40. + -. 2 ℃ C., 75%. + -. 5% RH), the results show that: the polymorphic form II is very stable, and compared with the newly prepared (month 0) polymorphic form II, the purity of the polymorphic form II is basically unchanged and is always over 99 percent, and no obvious degradation impurity is seen.
EXAMPLE 19 stability of polymorph III of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide hydrochloride
After 6 months of accelerated testing (test conditions 40. + -. 2 ℃ C., 75%. + -. 5% RH), the results show that: the polymorphic form III is very stable, and compared with newly prepared (month 0) polymorphic form III, the purity of the polymorphic form III is basically unchanged and is always over 99 percent, and no obvious degradation impurity is seen.
EXAMPLE 20 stability of polymorph IV of (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide hydrochloride
After 6 months of accelerated testing (test conditions 40. + -. 2 ℃ C., 75%. + -. 5% RH), the results show that: the polymorphic form IV is very stable, and compared with the newly prepared polymorphic form IV (month 0), the purity of the polymorphic form IV is basically unchanged and is always over 99 percent, and no obvious degradation impurity is seen.
EXAMPLE 21 stability of polymorph V of (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide
After 6 months of accelerated testing (test conditions 40. + -. 2 ℃ C., 75%. + -. 5% RH), the results show that: the polymorphic form V is very stable, and compared with the newly prepared (month 0) polymorphic form V, the purity of the polymorphic form V is basically unchanged and is always over 99 percent, and no obvious degradation impurity is seen.
EXAMPLE 22 pharmaceutical composition
Polymorph I of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride (examples 1 to 4) 200g
Starch 180g
Microcrystalline cellulose 40g
The materials are evenly mixed according to a conventional method and then are filled into common gelatin capsules to obtain 1000 capsules.
EXAMPLE 23 pharmaceutical composition
Polymorph II of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride monohydrate (examples 5-9) 200g
Starch 180g
Microcrystalline cellulose 40g
The materials are evenly mixed according to a conventional method and then are filled into common gelatin capsules to obtain 1000 capsules.
EXAMPLE 24 pharmaceutical composition
Polymorph III (examples 10 to 11) of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide hydrochloride 200g
Starch 180g
Microcrystalline cellulose 40g
The materials are evenly mixed according to a conventional method and then are filled into common gelatin capsules to obtain 1000 capsules.
EXAMPLE 25 pharmaceutical composition
Polymorph IV of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide hydrochloride salt (examples 12-14) 200g
Starch 180g
Microcrystalline cellulose 40g
The materials are evenly mixed according to a conventional method and then are filled into common gelatin capsules to obtain 1000 capsules.
EXAMPLE 26 pharmaceutical composition
Polymorph V of N- (cyanomethyl) -4- (2- (4- (morpholino) phenylamino) pyrimidin-4-yl) benzamide (examples 15-16) 200g
Starch 180g
Microcrystalline cellulose 40g
The materials are evenly mixed according to a conventional method and then are filled into common gelatin capsules to obtain 1000 capsules.
EXAMPLE 27 polymorph hygroscopicity test
The method is carried out according to the guiding principle of the drug hygroscopicity test (appendix XIX J of the second part of the 2010 version of the Chinese pharmacopoeia).
1. 4 dry glass weighing bottles with covers (external diameter 60mm, height 30mm) were taken and placed in a glass drier (constant temperature and humidity drier) with a saturated solution of ammonium sulfate placed at the lower part in a constant temperature and humidity chamber at 25 ℃. + -. 1 ℃ the day before the test.
2. After each empty weighing bottle together with the lid was placed in a "constant temperature and humidity dryer" for 24 hours, the respective weights were precisely stabilized in units of a jacket (weighing bottle + lid), and the weight was calculated as m 1.
3. Taking a proper amount of the polymorphic substance II sample, flatly placing the polymorphic substance II sample in a weighed glass weighing bottle (the thickness of the sample is about 1mm), covering the glass weighing bottle, precisely weighing the weight of each weighing bottle (the weighing bottle, the cover and the sample) at the moment, and counting as m 2.
3. After each sample was left in the "constant temperature and humidity dryer" for 24 hours, the weight of each weighing bottle (weighing bottle + cap + sample) at that time was precisely weighed and was m 3.
4. The percent moisture wicking weight gain was calculated for each sample (formula below) and was defined as no or almost no moisture wicking when the percent moisture wicking weight gain was less than 0.2%. When the percentage of moisture-attracting weight gain is 0.2% or more but less than 2.0%, the coating is defined as slightly hygroscopic.
Percent weight gain [ (m3-m2)/(m2-m1) ] x 100%
The hygroscopicity of the polymorph II according to the present invention was determined according to the above procedure, and the results showed that: the weight gain percentage of polymorph II [ (35.2607-35.2566)/(35.2566-34.1458) ] × 100 ═ 0.37%. As can be seen, polymorph II is slightly hygroscopic.
The procedure of example 27 was repeated except that polymorphic forms I, III-V of the present invention were used in place of polymorphic form II, and it was found that the various polymorphic forms of the present invention were all very stable, substantially free of hygroscopicity, and only polymorphic form I was slightly hygroscopic.
Thus, the polymorph according to the invention is very suitable for use in pharmaceutical compositions. In addition, the polymorphic substance is not easy to raise, collect and waste in the manufacturing process of split charging and other medicines, and is beneficial to protecting the health of operators.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (8)
1. A polymorph form II of a monohydrate of the dihydrochloride of the compound of formula I, wherein the polymorph form II has X-ray powder diffraction characteristic peaks as shown below: 9.220, 13.253, 17.310 +/-0.2, 18.553 +/-0.2, 16.699 +/-0.2, 22.643 +/-0.2, 23.964, 24.617 +/-0.2, 15.278 +/-0.2, 25.600 +/-0.2, 27.119 +/-0.2, 30.282 +/-0.2 and 12.141 +/-0.2,
formula I.
2. The polymorph of claim 1, wherein the polymorph II has X-ray powder diffraction characteristic peaks substantially as shown in figure 2 a.
3. The polymorph of claim 1, wherein the polymorph form II exhibits a differential scanning calorimetry pattern having maximum peaks at 140.87 ℃ ± 2 ℃, 182.2 ℃ ± 2 ℃ and 234.34 ℃ ± 2 ℃.
4. The polymorph of claim 1, wherein the polymorph II has a differential scanning calorimetry trace substantially as shown in figure 2 b.
5. Use of a polymorph according to any one of claims 1 to 4 for the preparation of a pharmaceutical composition of a non-receptor tyrosine kinase.
6. The use of claim 5, wherein the non-receptor tyrosine kinase comprises a JAK kinase.
7. A pharmaceutical composition, comprising:
(a) the polymorph of any one of claims 1 to 4; and
(b) a pharmaceutically acceptable carrier.
8. A process for the preparation of the polymorph according to any one of claims 1 to 4, comprising the steps of: crystallizing a compound of formula I and hydrochloric acid as a salt in a mixed solvent of dimethyl sulfoxide and ethanol, or a mixed solvent of dimethyl sulfoxide and acetone to obtain the polymorph of any one of claims 1 to 4.
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| PCT/CN2016/087093 WO2016206634A1 (en) | 2015-06-26 | 2016-06-24 | Morpholino phenyl amino pyrimidine compound or polymorph of salt thereof |
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| WO2009073575A2 (en) * | 2007-11-30 | 2009-06-11 | Oregon Health & Science University | Methods for treating induced cellular proliferative disorders |
| CN101861313A (en) * | 2007-03-12 | 2010-10-13 | 西托匹亚研究有限公司 | Phenyl amino pyrimidine compounds and uses thereof |
| CN103370068A (en) * | 2010-12-03 | 2013-10-23 | Ym生物科学澳大利亚私人有限公司 | Treatment of JAK2-mediated conditions |
| CN103533939A (en) * | 2011-05-02 | 2014-01-22 | 澳大利亚Ym生物科学私人有限公司 | Multiple myeloma treatment |
| CN106458929A (en) * | 2014-06-12 | 2017-02-22 | 吉利德科学公司 | N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide hydrochloride salts |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101861313A (en) * | 2007-03-12 | 2010-10-13 | 西托匹亚研究有限公司 | Phenyl amino pyrimidine compounds and uses thereof |
| WO2009073575A2 (en) * | 2007-11-30 | 2009-06-11 | Oregon Health & Science University | Methods for treating induced cellular proliferative disorders |
| CN103370068A (en) * | 2010-12-03 | 2013-10-23 | Ym生物科学澳大利亚私人有限公司 | Treatment of JAK2-mediated conditions |
| CN103533939A (en) * | 2011-05-02 | 2014-01-22 | 澳大利亚Ym生物科学私人有限公司 | Multiple myeloma treatment |
| CN106458929A (en) * | 2014-06-12 | 2017-02-22 | 吉利德科学公司 | N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide hydrochloride salts |
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