Salt of EGFR inhibitor, crystalline form and uses thereof

Abstract

The invention relates to a salt, a hydrate or a crystalline form of an EGFR inhibitor, and use thereof. Specifically it relates to 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-[3-[(1R,6S)-2,5-dioxa-8-azabicyclo [4.3.0] nonan-8-yl] propoxy] quinazoline dimethanesulfonate, hydrate and a crystalline form thereof; the invention also relates to a preparation method of the crystalline form disclosed herein, a pharmaceutical composition containing the crystalline form, and uses thereof for treating proliferative disorders.

Claims

1. A compound having Formula (I): ##STR00005##

2. A hydrate of a compound having formula (I). ##STR00006##

3. The hydrate of claim 2, wherein the hydrate is a monohydrate of the compound having formula (I).

4. A crystalline form of a monohydrate of a compound having formula (I): ##STR00007## wherein the crystalline form is form I having one or more of following characteristics: i) an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2 at 14.880.2, 18.050.2, 20.840.2, 21.340.2, 24.390.2 and 25.180.2; or/and ii) the following structure parameters analyzed from monocrystalline: TABLE-US-00008 Crystallographic System: monoclinic system Space Groups: C2/c; Cell Parameters: a = 27.3004(5) , = 90, b = 16.2882(3) , = 103.3439(17), c = 14.3529(2) , = 90; Volume: 6210.01(18) .sup.3; Molecules number of 8. each unit cell (Z):

5. The crystalline form of claim 4 having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2 at 9.470.2, 14.880.2, 16.580.2, 17.150.2, 17.460.2, 18.050.2, 20.460.2, 20.840.2, 21.340.2, 22.710.2, 23.160.2, 24.390.2, 25.180.2, 25.460.2, 26.290.2 and 28.010.2.

6. The crystalline form of claim 4 having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2 at 6.360.2, 6.660.2, 9.470.2, 10.820.2, 11.700.2, 13.310.2, 14.880.2, 15.860.2, 16.580.2, 17.150.2, 17.460.2, 18.050.2, 19.300.2, 20.460.2, 20.840.2, 21.340.2, 21.760.2, 22.280.2, 22.710.2, 23.160.2, 24.070.2, 24.390.2, 25.180.2, 25.460.2, 26.290.2, 26.780.2, 27.150.2, 28.010.2, 28.800.2, 29.770.2, 30.440.2, 31.060.2, 32.050.2, 33.010.2, 33.510.2, 33.840.2, 34.900.2, 38.030.2, 38.580.2 and 39.480.2.

7. The crystalline form of claim 4 having an X-ray powder diffraction (XRPD) pattern as shown in FIG. 1.

8. The crystalline form of claim 4 having a monocrystalline structure as shown in FIG. 3.

9. A pharmaceutical composition comprising the compound of claim 1, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

10. The pharmaceutical composition of claim 9 further comprising a therapeutic agent, wherein the therapeutic agent is a chemotherapeutic agent used for treating proliferative disease or cancer, an antiproliferative agent, a cytotoxic agent, a signal transduction inhibitor, an agent used for treating non-small cell lung cancer or skin cancer or a combination thereof; and wherein the therapeutic agent is adriamycin, rapamycin, temsirolimus, everolimus, ixabepilone, gemcitabine, cyclophosphamide, dexamethasone, etoposide, fluorouracil, imatinib mesylate, dasatinib, nilotinib, erlotinib, lapatinib, gefitinib, sorafenib, sunitinib, interferon, carboplatin, topotecan, paclitaxel, vinblastine, vincristine, temozolomide, tositumomab, trabedectin, bevacizumab, trastuzumab, cetuximab, panitumumab, icotinib, icotinib hydrochloride, matuzmab, neratinib, canertinib, vandetanib, cediranib, vatalanib, axitinib, motesanib, nimotuzumab, theliatinib, epitinib, simotinib, poziotinib, varlitinib, rociletinib, pelitinib, osimertinib, PKI-166, PD 158780, MDX447, Mab425, HM-61713, TAS-121, seribantumab, naquotinib, or a combination thereof.

11. A method of inhibiting EGFR in a subject, comprising administering to the subject a therapeutically effective amount of the compound of claim 1.

12. A method of treating a proliferative disorder in a patient, comprising administering to the patient a therapeutically effective amount of the compound of claim 1; wherein the proliferative disorder is colon cancer lung cancer or malignant glioma.

13. A pharmaceutical composition comprising the hydrate of claim 2; and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

14. A pharmaceutical composition comprising the crystalline form of claim 4; and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

15. The pharmaceutical composition of claim 13 further comprising a therapeutic agent, wherein the therapeutic agent is a chemotherapeutic agent used for treating proliferative disease or cancer, an antiproliferative agent, a cytotoxic agent, a signal transduction inhibitor, an agent used for treating non-small cell lung cancer or skin cancer or a combination thereof; and wherein the therapeutic agent is adriamycin, rapamycin, temsirolimus, everolimus, ixabepilone, gemcitabine, cyclophosphamide, dexamethasone, etoposide, fluorouracil, imatinib mesylate, dasatinib, nilotinib, erlotinib, lapatinib, gefitinib, sorafenib, sunitinib, interferon, carboplatin, topotecan, paclitaxel, vinblastine, vincristine, temozolomide, tositumomab, trabedectin, bevacizumab, trastuzumab, cetuximab, panitumumab, icotinib, icotinib hydrochloride, matuzmab, neratinib, canertinib, vandetanib, cediranib, vatalanib, axitinib, motesanib, nimotuzumab, theliatinib, epitinib, simotinib, poziotinib, varlitinib, rociletinib, pelitinib, osimertinib, PKI-166, PD 158780, MDX447, Mab425, HM-61713, TAS-121, seribantumab, naquotinib, or a combination thereof.

16. The pharmaceutical composition of claim 14 further comprising a therapeutic agent, wherein the therapeutic agent is a chemotherapeutic agent used for treating proliferative disease or cancer, an antiproliferative agent, a cytotoxic agent, a signal transduction inhibitor, an agent used for treating non-small cell lung cancer or skin cancer or a combination thereof; and wherein the therapeutic agent is adriamycin, rapamycin, temsirolimus, everolimus, ixabepilone, gemcitabine, cyclophosphamide, dexamethasone, etoposide, fluorouracil, imatinib mesylate, dasatinib, nilotinib, erlotinib, lapatinib, gefitinib, sorafenib, sunitinib, interferon, carboplatin, topotecan, paclitaxel, vinblastine, vincristine, temozolomide, tositumomab, trabedectin, bevacizumab, trastuzumab, cetuximab, panitumumab, icotinib, icotinib hydrochloride, matuzmab, neratinib, canertinib, vandetanib, cediranib, vatalanib, axitinib, motesanib, nimotuzumab, theliatinib, epitinib, simotinib, poziotinib, varlitinib, rociletinib, pelitinib, osimertinib, PKI-166, PD 158780, MDX447, Mab425, HM-61713, TAS-121, seribantumab, naquotinib, or a combination thereof.

17. A method of inhibiting EGFR in a subject, comprising administering to the subject a therapeutically effective amount of the crystalline form of claim 4.

18. A method of inhibiting EGFR in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 14.

19. A method of treating the severity of a proliferative disorder in a patient, comprising administering to the patient a therapeutically effective amount of the crystalline form of claim 4, wherein the proliferative disorder is colon cancer lung cancer, or malignant glioma.

20. A method of treating a proliferative disorder in a patient, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 14; wherein the proliferative disorder is colon cancer, lung cancer, or malignant glioma.

Description

DESCRIPTION OF THE FIGURES

(1) FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of crystalline form I according to example 1;

(2) FIG. 2 shows a thermogravimetric analysis (TGA) curve of crystalline form I according to example 1; and

(3) FIG. 3 shows a single-crystal structure of crystalline form I of the invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

(4) The invention is further illustrated by the following examples, which are not be construed as limiting the invention in scope.

(5) The X-Ray powder Diffraction (XRPD) analysis method of the present invention examples comprises recording an X-ray powder diffraction diagram on a PANalytical Empyrean X-ray diffractometer using Cu-K radiation (45 KV, 40 mA). A thin layer is prepared from powder sample on the single-crystal silicon wafer, and a sample spinner is used. The angular range extends from 3 to 40 in 2 with a 0.0168 step size in 2. Data are collected by Data Collector software, and processed by HighScore Plus software, read by Data Viewer software.

(6) Thermogravimetric Analysis (TGA): Thermogravimetric curve is recorded on a TA Q500 instrument with a thermoanalysis controller. The data are collected and analyzed by TA Instruments Thermal Solutions software. About 10 mg sample is weighed accurately in platinum sample pans, then heated from ambient temperature to 350 C. using a linear heating device at a scan rate of 10 C./minute for sample analysis. During the period of sample analysis, TGA furnace chamber is purged by dry nitrogen.

(7) X-Ray Single-crystal diffractometer of the present invention examples: Single-crystal X-ray diffraction pattern is recorded on an Agilent Technologies Gemini A Ultra X-ray diffractometer using Cu-K radiation (40 KV, 40 mA) and w-scan, the total number of diffraction counts is 1145, analyzing the crystallography data tables and single-crystal structure by SHELXTL software.

(8) The purity of the compound used in the stability test or accelerated test is measured by Aglient 1200 high performance liquid chromatography with VWD detector. The chromatographic column model is ZORBAX Extend-C18 (4.6150 mm, 5 M), the detection wavelength is 250 nm, the flow rate is 1.0 mL/min, the column temperature is 40 C., and the mobile phase is 10 mM KH.sub.2PO.sub.4 (pH=7.5)-acetonitrile (v/v=55/45).

(9) The preparation method of crystalline form I and experimental evaluation of crystalline form I will be described detailedly below.

(10) The specific preparation method of 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-[3-[(1R,6S)-2,5-dioxa-8-azabicyclo[4.3.0]nonan-8-yl]propoxy]quinazoline can refer to the preparation method of example 6 disclosed in patent CN 103102344 A (publication number).

Example 1

(11) 1. Preparation of crystalline form I of 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-[3-[(1R,6S)-2,5-dioxa-8-azabicyclo[4.3.0]nonan-8-yl]propoxy]quinazoline dimethanesulfonate monohydrate

(12) To a solution of methanesulfonic acid (0.173 g, 1.803 mmol) in methanol (10 mL) was added a solution of 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-[3-[(1R,6S)-2,5-dioxa-8-azabicyclo[4.3.0]nonan-8-yl]propoxy]quinazoline (0.40 g, 0.819 mmol) in methanol (30 mL) at rt. The mixture was stirred at 60 C. overnight. The mixture was concentrated in vacuo to remove the solvent. The residue was triturated by a large amount of ethyl acetate to give a white solid (519 mg, 93.01%).

(13) 2. Identification of crystalline form I of 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-[3-[(1R,6S)-2,5-dioxa-8-azabicyclo[4.3.0]nonan-8-yl]propoxy]quinazoline dimethanesulfonate monohydrate

(14) 1) The salt-forming ratio was 1:2 determined by .sup.1H NMR.

(15) 2) The XRPD pattern analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) with Cu-K radiation had the following characteristic peaks expressed in degrees 2 at 6.36, 6.66, 9.47, 10.82, 11.70, 13.31, 14.88, 15.86, 16.58, 17.15, 17.46, 18.05, 19.30, 20.46, 20.84, 21.34, 21.76, 22.28, 22.71, 23.16, 24.07, 24.39, 25.18, 25.46, 26.29, 26.78, 27.15, 28.01, 28.80, 29.77, 30.44, 31.06, 32.05, 33.01, 33.51, 33.84, 34.90, 38.03, 38.58 and 39.48. The error margin in 2 of the characteristic peaks was 0.2 (as shown in FIG. 1).

(16) 3) The TGA curve was analyzed and identified by using TA Q500 thermal gravity analysis (TGA) with a scan rate of 10 C./minute at a temperature range of 25 C.150 C., the weight loss ratio was 3.234%. The error margin in the weight loss ratio was 0.1%; the sample lost crystal water at a temperature range of 79 C.161 C., and the loss weight was consistent with the theoretical value of crystallization water content (2.577%) (as shown in FIG. 2).

(17) 4) The parameters of the single monocrystalline measured by detection of monocrystalline were listed in table 1, and the monocrystalline structure was as shown in FIG. 3.

(18) TABLE-US-00001 TABLE 1 The parameters of the single monocrystalline Crystallographic System: monoclinic system Space Groups: C2/c Cell Parameters: a = 27.3004(5) , = 90, b = 16.2882(3) , = 103.3439(17), c = 14.3529(2) , = 90 Volume: 6210.01(18) .sup.3 Molecules number of 8 each unit cell (Z):

Example 2 Pharmacokinetic Assay

(19) The pharmacokinetic properties of the compound of Formula (II) and crystalline form I of the invention were assessed in beagle dogs: each group having 3 beagle dogs was administered by oral in a capsule form. The dosage amount of crystalline form I was converted and determined according to the compound of Formula (II) at a dosage of 5 mg/kg. Results were as shown below.

(20) TABLE-US-00002 TABLE 2 In vivo Pharmacokinetic parameters of beagle dogs C.sub.max AUC.sub.last AUC.sub.inf T.sub.1/2 Compound T.sub.max (h) (ng/ml) (ng .Math. h/ml) (ng .Math. h/ml) (h) Compound of 1.67 125.37 825.31 886.11 3.62 Formula (II) Crystalline form I 1.33 231.43 1446.44 1465.11 3.65

(21) Conclusion: crystalline form I of 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-[3-[(1R,6S)-2,5-dioxa-8-azabicyclo[4.3.0]nonan-8-yl]propoxy]quinazoline dimethanesulfonate monohydrate had better bioavailability than compound of Formula (II). Individual data analysis of beagle dog showed that crystalline form I had a higher exposure level and a faster absorption in dogs, and the Tmax time of crystalline form I was earlier than compound of Formula (II).

Example 3 Hygroscopic Test

(22) 1. Instruments: one hundred thousandth electronic balance, type: XP205DR, manufacturer: Mettler.

(23) 2. Test method deriving from Chinese Pharmacopoeia 2010, appendix XIX J: Guideline on pharmaceutical hygroscopic test. Specific method is described as follows:

(24) 1) Placing a dried glass-stoppered, weighing bottle (outer diameter: 50 mm, height: 15 mm) in a thermostatic drier with saturated aqueous ammonium chloride or ammonium sulfate solution in the bottom at the previous day of the test maintaining the temperature at 25 C.1 C., and the glass-stoppered, weighing bottle was weighed precisely.

(25) 2) Taking and weighing an appropriate amount of the sample (m.sub.1), and placing the sample into the weighing bottle with thickness of about 1 mm.

(26) 3) Opening the weighing bottle, and placing the glass stopper with the opened weighing bottle in a constant temperature and humidity condition for 24 h.

(27) 4) Sealing the weighing bottle with glass stopper, and the weighing bottle sealed with glass stopper was weighed precisely (m.sub.2). The percentage (%) of weight gain was calculated.
Percentage (%) of weight gain=(m.sub.2m.sub.1m.sub.0)/m.sub.1100%

(28) 5) The hygroscopic features and definition of hygroscopic weight gain are summarized in table 3 (deriving from Chinese Pharmacopoeia 2010, appendix XIX J: Guideline on pharmaceutical hygroscopic test, test conditions: 25 C.1 C., Relative Humidity 80%2%).

(29) TABLE-US-00003 TABLE 3 The hygroscopic features and definition of hygroscopic weight gain The percentage (%) of hygroscopic Hygroscopic features weight gain 1 Deliquescence Absorbing enough water to form liquid 2 High The weight increase of the hygroscopicity hygroscopicity is no less than 15% 3 Having The weight increase of the hygroscopicity hygroscopicity is between 15% and 2% 4 Slight The weight increase of the hygroscopicity hygroscopicity is between 2% and 0.2% 5 No or almost no The weight increase of the hygroscopicity hygroscopicity is no less than 0.2%

(30) 3. Results

(31) The results were shown in table 4.

(32) TABLE-US-00004 TABLE 4 Hygroscopic test results Hygroscopic m.sub.0 (g) m.sub.1 (g) m.sub.2 (g) weight gain 30.51893 0.99751 31.51718 0.074%

(33) Conclusion: The weight of crystalline form I of 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-[3-[(1R,6S)-2,5-dioxa-8-azabicyclo[4.3.0]nonan-8-yl]propoxy]quinazoline dimethanesulfonate monohydrate gained 0.074% after placing crystalline form I at a relative humidity of 80%2% for 24 h. According to the definition of hygroscopic weight gain, crystalline form I has almost no hygroscopicity.

Example 4 Stability Test

(34) According to Guidelines for the stability test of raw materials and preparations (Chinese Pharmacopoeia, 2015, 4th edition, general rules 9001), the stability of crystalline form I was tested as follows:

(35) Appropriate amount of sample was taken into the flat weighing bottle to form a thin layer of no more than 5 mm thick. Then the stability of crystalline form I was tested under the conditions showed in table 5. The content of impurities was tested by HPLC.

(36) TABLE-US-00005 TABLE 5 Stability test method Inspection Project Test condition sampling point project High 60 C. 2 C. 0, 5, 10 days Impurities temperature High 25 C. 2 C./92.5% RH 0, 5, 10 days humidity Illumination Visible light illumination: 0, 5, 10, 15 days 4500 500 lx, UV intensity: not less than 0.7 W .Math. h/m.sup.2

(37) The results were shown in table 6.

(38) TABLE-US-00006 TABLE 6 The results of stability test High High Condition temperature humidity Illumination 0 5 10 5 10 5 10 15 Project day days days days days days days days Crystalline 0.13 0.12 0.14 0.14 0.16 0.13 0.13 0.14 form I Impurities (total impurities, %)

(39) Conclusion: The impurity of crystalline form I of 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-[3-[(1R,6S)-2,5-dioxa-8-azabicyclo[4.3.0]nonan-8-yl]propoxy]quinazoline dimethanesulfonate monohydrate had no obvious change at high temperature for 10 days, or under high humidity for 10 days or under illumination condition for 15 days, thereby the quality of crystalline form I is stable under high temperature condition, high humidity condition or illumination condition.

Example 5 Accelerated Test

(40) According to Guidelines for the stability test of raw materials and preparations (Chinese Pharmacopoeia, 2015, 4th edition, general rules 9001), the accelerated test of crystalline form I was practiced as follows:

(41) Medicinal low density polyethylene bag (the size was 140*120*0.104 mm.sup.3, the manufacture was Tianjin Litian Medicine Packing Material Co., Ltd, and the batch number was 121238.) was used as inner package material, and the bag was sealed by nylon cable ties; and paper tube was used as a packaging material. The packaged samples were placed in a constant temperature and humidity test chamber (402 C./75%5% RH) for six months for accelerated test. Sampling at the end of 1, 2, 3 or 6 months for testing the moisture content of the sample by using karl fischer titration, the content of impurities was measured by HPLC.

(42) The test results were shown in table 7.

(43) TABLE-US-00007 TABLE 7 Results of Accelerated test Project Moisture (%) Impurities (total impurities, %) Time 0 day 2.79 0.18 One month 2.92 0.18 Two months 2.87 0.17 Three months 3.09 0.18 Six months 2.86 0.17

(44) Conclusions:

(45) (1) Impurity had no obvious change in the progress of accelerated test, and the property of sample was stable under the packaging condition, without degradation.

(46) (2) Moisture had no obvious change in the progress of accelerated test, and the sample wasn't hygroscopic under the packaging condition.

(47) The results of the accelerated test showed that, the quality of crystalline form I of 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-[3-[(1R,6S)-2,5-dioxa-8-azabicyclo[4.3.0]nonan-8-yl]propoxy]quinazoline dimethanesulfonate monohydrate was stable under the accelerated test condition for six months using medicinal low density polyethylene bag as inner package material.

(48) The foregoing has described the invention including basic instructions. Any equivalent alterations according the technology of the present invention that would be apparent to the skilled person are within the scope of the invention.

(49) Reference throughout this specification to an embodiment, some embodiments, one embodiment, another example, an example, a specific examples, or some examples, means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present disclosure. Thus, the appearances of the phrases such as in some embodiments, in one embodiment, in an embodiment, in another example, in an example, in a specific examples, or in some examples, in various places throughout this specification are not necessarily referring to the same embodiment or example of the present disclosure. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments or examples. In addition, those skilled in the art can integrate and combine different embodiments, examples or the features of them as long as they are not contradictory to one another.

(50) Although explanatory embodiments have been shown and described, it would be appreciated by those skilled in the art that the above embodiments cannot be construed to limit the present disclosure, and changes, alternatives, and modifications can be made in the embodiments without departing from spirit, principles and scope of the present disclosure.