WO2016019909A1 - New crystal form of anticancer compound, preparation method and use thereof - Google Patents

Abstract

Disclosed are a crystal form of an anticancer compound (R)-3-[1-(2, 6-dichloro-3-fluorophenyl) ethoxy]-5-[3-fluorophenyl-1-dimethyl phosphine acyl-oxy-4-yl] pyridine-2-amine and preparation method thereof. The structural formula of the crystal form is as represented by formula I. The crystal form has a stable property, a high purity, no hygroscopicity and high bioavailability, and meets requirements for pharmaceutical preparation.

Description

Novel crystal form of anticancer compound, preparation method and use thereof Technical field

The invention relates to the field of medicinal chemical industry, in particular to an anticancer compound (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl Crystal form of 1-dimethylphosphonooxy-4-yl]pyridin-2-amine and preparation method thereof.

Background technique

Lung cancer is the most common primary malignant tumor of the lung and is usually classified into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Lung cancer is the cancer with the highest morbidity and mortality. Non-small cell lung cancer accounts for 80% to 85% of the total number of lung cancers, and its mortality rate is as high as 80% to 90%. According to the statistics of the World Health Organization (WHO), there were 1,332,132 new cases of lung cancer in 2002, accounting for 12.4% of the total number of new cancer cases, ranking first, the third time announced by the Ministry of Health of China on April 29, 2008. The main results of the national death cause survey show that the mortality rate of lung cancer in China has increased by 465% in the past 30 years. At present, lung cancer has replaced liver cancer as the cause of death in the first malignant tumor in China, accounting for 22.7% of malignant tumor deaths.

The 5-year survival rate of lung cancer in developed countries is about 10% to 15%, which is lower in China. If the advanced NSCLC is not treated, the median survival time is about 4 to 5 months, and the 1-year survival rate is less than 10%. The standard first-line chemotherapy regimen of advanced NSCLC is equivalent to the best supportive treatment, which can effectively prolong the median survival time and increase the 1-year survival period. Survival rate. However, the current efficacy of chemotherapy seems to reach a platform, its objective efficiency is about 30%, the median survival time is 8 to 9 months, and the 1-year survival rate is 30% to 40%. Therefore, finding more effective and safe treatments has become a hot spot in current lung cancer research. Tumor molecular targeted therapy is a treatment for other biological pathways. At present, NSCLC's targeted therapeutic drugs mainly include epidermal growth factor receptor (EGFR) family inhibitors, angiogenesis inhibitors, multi-target inhibitors, signal transduction inhibitors, and apoptosis inducers. Professor Ma Jun, the chairman of the Executive Committee of the Clinical Oncology Collaborative Professional Committee (CSCO) of China Anti-Cancer Association, and the famous clinical oncologist, pointed out: "Because of the early concealment, most patients with non-small cell lung cancer have been locally late or have occurred. Transfer, more than half of lung cancer patients will miss the opportunity for surgery. Traditional radiotherapy and chemotherapy has limited efficacy and is difficult to accompany The more toxic side effects of the drug, the more often the failure of radiotherapy and chemotherapy, the worse the effect of subsequent treatment. However, the emergence of targeted drugs provides a new possibility for conquering lung cancer. ”

Pfizer announced on August 26, 2011 that the company's XALKORI (crizotinib) capsule was approved by the US Food and Drug Administration for FDA approval, the first drug to target anaplastic lymphoma kinase (ALK). Locally advanced or metastatic non-small cell lung cancer diagnosed as ALK positive was diagnosed by an FDA-approved test. The efficacy of XALKORI is based on objective response rate (ORR). While XALKORI has received rapid FDA approval, Pfizer is conducting a post-marketing clinical trial to further evaluate the clinical efficacy of XALKORI. Based on FDA's latest guidance on targeted therapy and companion diagnostics, Pfizer has worked closely with the FDA and Abbott Molecular Diagnostics Business Units in clinical trials to ensure that XALKORI and Abbott's diagnostic testing technologies are reviewed and approved at the same time. The latter is the Vysis ALK Break Apart FISH probe kit from the Abbott Molecular Diagnostics business unit to discover the ALK fusion gene. XALKORI and the Abbott Molecular Diagnostics Business Unit's ALK FISH kit were also approved, and it also marks the first development and approval of Pfizer's oncology drug or tumor treatment program along with the diagnostic test protocol. “By truly understanding NSCLC's driver genes, such as ALK, we can select the patients most likely to respond to treatment. XALKORI provides us with a new path to explore future drug development and cancer treatment,” University of Colorado, Denver Cancer Research The heads of Professor Paul Bunn and the chief physician of James Dudley pointed out. “XALKORI is the first new drug to treat lung cancer approved by the FDA for more than 6 years, representing a shift in the treatment of non-small cell lung cancer. We are moving from a monolithic treatment regime to a treatment model through biomarker decision-making.” In the XALKORI clinical trial In the test protocol, the biomarker ALK fusion gene test result of the patient's tumor is positive to improve the possibility of responding to the treatment. This first test for lung cancer treatment allows researchers to observe good results in pre-screened patient populations. Preliminary epidemiological studies have shown that the ALK positive rate in non-small cell lung cancer is approximately 3-5%, meaning that there are approximately 650 to 11,000 ALK-positive non-small cell lung cancer patients in the United States each year. Targeted response to XALKORI-registered clinical trials, in patients with advanced ALK-positive non-small cell lung cancer, the objective response rate was 50 to 61%.

Experts predict that China's non-small cell lung cancer (NSCLC) treatment market will more than double in the 2008-2013 period, from $307 million to $648 million. Colorectal cancer case treatment The increase in treatment will accelerate this growth. Urbanization and population aging will lead to a 47% increase in the incidence of non-small cell lung cancer in China between 2008 and 1818, from 361,500 to 531,300. The most obvious growth will occur in cities, where non-small cell lung cancer cases will increase by 72% in the next decade, while rural areas have only 8% growth. Gefitinib (Israel's Iressa), erlotinib (Roche's Tarceva), and endostatin (Jiangsu Xiansheng Pharmaceutical's Endo) and other targeted therapies are becoming more popular, and new targets The introduction of therapeutic drugs – bevacizumab (Ross Avastin) and cetuximab (Merck's Erbitux) – are the main forces driving the Chinese non-small cell lung cancer market during 2008-2013. The market share of multinational companies in China for non-small cell lung cancer treatment will rise from 34% in 2008 to 47% in 2013. This increase will be driven primarily by increased introduction of targeted drugs. Due to fierce competition at low prices, multinational companies' chemotherapy drugs will lose their market in China. Therefore, as a "me too" drug for Crizotinib, the compound of formula I will have broad market potential.

Drug crystal research and solid-state drug development are of paramount importance in the pharmaceutical industry. Drug molecules usually have different solid forms, including salts, polycrystals, eutectic, amorphous, hydrates and solvates; different crystal forms of the same drug molecule, in crystal structure, stability, manufacturability and bioavailability There may be significant differences in the nature of the degree, which directly affects the efficacy and developability of the drug. Therefore, any drug development requires a comprehensive system of polymorphic screening to find as many crystal forms as possible, and then use various solid-state methods to conduct in-depth research on these crystal forms to find the most suitable crystal form.

Summary of the invention

It is an object of the present invention to provide a crystalline form of a compound of formula I which exhibits a diffraction peak at 2θ (± 0.2°) of 6.63, 7.64, 10.38, 11.38, 12.07, 13.23, 15.48, 16.90,

Preferably, the crystalline XRPD pattern also exhibits a diffraction peak at 2θ (±0.2°) of 19.47, 20.06, 20.83, 22.43, 24.26, 26.18, 29.74.

Particularly preferably, the crystalline XRPD pattern is shown in Figure 1.

The crystal form of the present invention was subjected to thermogravimetric analysis (TGA) to show that the sample was kept constant from room temperature to 220 ° C, indicating that the sample contained no crystal water or an adsorption solvent. Then the sample began to lose weight. The sample weight loss was severe at around 260 °C, and the weight loss slowed down at about 400 °C, and the weight loss to 700 °C was about 62%.

The crystal form of the present invention exhibits an endothermic peak in the range of 180 ° C to 185 ° C by differential scanning calorimetry (DSC) and has a sharp absorption peak at 182 ± 1 ° C.

It is also an object of the present invention to provide a process for preparing the crystalline form comprising dissolving a compound of formula I with an organic solvent, cooling and crystallization by stirring, and filtering to obtain a target crystalline form.

Another object of the present invention is to provide an alternative method of preparing the crystalline form comprising dissolving a compound of formula I with an organic solvent, adding an anti-solvent to agitate the crystal, and filtering to obtain a target crystalline form.

Further, in the above preparation process, after the crystallization filtration, a drying step is further included, and the drying temperature is 25 ° C or higher, preferably 70 ° C or higher, more preferably 80 ° C or higher.

Preferably, the organic solvent is selected from the group consisting of acetonitrile, ethyl acetate and/or butyl acetate.

Preferably, the anti-solvent is selected from the group consisting of isopropyl ether, n-heptane and/or n-hexane.

It is still another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form and a pharmaceutically acceptable carrier.

Another object of the present invention is to provide the use of the crystalline form or the pharmaceutical composition for the preparation of an antitumor drug

The crystal form provided by the invention has high purity, good stability, no hygroscopicity and high bioavailability, and is suitable for medical preparations.

DRAWINGS

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethylphosphonooxylate of the present invention. XRPD pattern of the crystalline form of 4-yl]pyridin-2-amine.

Figure 2 is a (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethylphosphonooxylate of the present invention. Thermogravimetric analysis (TGA) of the crystalline form of 4-yl]pyridin-2-amine.

Figure 3 is a (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethylphosphonooxylate of the present invention. Differential Scanning Thermogram (DSC) of the crystalline form of 4-yl]pyridin-2-amine.

detailed description

Example 1

5.0 g of the crude compound of the formula I was poured into 70 ml of acetonitrile, stirred and dissolved in a water bath at 70 ° C, and then naturally cooled and stirred for 2 h. Filtration, vacuum drying at 25 ° C to obtain the target crystal form 3.1 g, after testing, its XRPD spectrum is shown in Figure 1.

Example 2

5.0 g of the crude compound of the formula I was poured into 100 ml of ethyl acetate, stirred and dissolved in a water bath at 65 ° C, and then naturally cooled and stirred for 2 h. Filtration, vacuum drying at 25 ° C to obtain the target crystal form 3.5g, after testing, its XRPD pattern is basically consistent with Figure 1, all characteristic peaks are within the error range.

Example 3

5.0 g of the crude compound of the formula I was poured into 175 ml of ethyl acetate, and dissolved by stirring in a water bath at 60 ° C, and then isopropyl ether was added and stirred for 2 h. Filtration, vacuum drying at 25 ° C to obtain the target crystal form 4.3 g, after testing, its XRPD pattern is basically consistent with Figure 1, all characteristic peaks are within the error range.

Example 4

5.0 g of the crude compound of the formula I was poured into 175 ml of ethyl acetate, dissolved by stirring in a water bath at 60 ° C, and then stirred and crystallized for 2 h by adding n-heptane. Filtration, vacuum drying at 25 ° C to obtain the target crystal form 4.7g, after testing, its XRPD pattern is basically consistent with Figure 1, all characteristic peaks are within the error range.

Example 5

5.0 g of the crude compound of the formula I was poured into 42 ml of acetone, stirred and dissolved in a water bath at 60 ° C, and then naturally cooled and stirred for 2 h. Filtration and vacuum drying at 80 ° C for 18 hours or more gave 4.2 g of the target crystal form. After testing, its XRPD pattern is basically consistent with Figure 1, and all characteristic peaks are within the error range.

Experimental Example I. Thermal Stability Study

Appropriate amount of the crystal form of the present invention was placed under different temperature conditions, and samples were taken after 18 hours to detect X-ray powder diffraction. The results are shown in Table 1:

Table 1

As can be seen from the above table, the present invention (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethylphosphine The X-ray powder diffraction pattern of the acyloxy-4-yl]pyridin-2-amine crystal form did not change significantly under different temperature conditions, indicating that the crystal form did not change, indicating good thermal stability.

Experimental example 2, influencing factors test

Appropriate amount of the crystal form of the invention is placed under the conditions of high temperature 60 ° C, high humidity RH 92.5%, strong light 4500 lx, and samples are taken on the 0th, 5th, and 10th days, and the sample is tested for dry weight loss, maximum single impurity, total impurity, The isomers and content, the test results are shown in Table 2.

Table 2

Experimental Example 3, Accelerated Test

An appropriate amount of the crystal form of the present invention was placed at a temperature of 40 ° C ± 2 ° C and a relative humidity of 75% ± 5% for 6 months. Samples were taken at 0, 1, 2, 3, and 6 months, and the samples were tested for dry weight loss, maximum single heterogeneity, total impurities, isomers, and content. The test results are shown in Table 3.

table 3

Experimental example 4, long-term test

An appropriate amount of the crystal form of the present invention is placed at a temperature of 30 ° C ± 2 ° C and a relative humidity of 65% ± 5% for 24 months. Samples were taken at 0, 3, 6, 9, 12, 18, and 24 months, and the samples were tested for dry weight loss, maximum single heterogeneity, total impurities, isomers, and content. The test results are shown in Table 4.

Table 4

As can be seen from Table 2-4, (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-di of the present invention The methylphosphonooxy-4-yl]pyridin-2-amine crystal form compound showed no significant change in the high temperature, high humidity, strong light and accelerated 6 months and long-term 24 months test. The sample quality is stable and controllable, the stability is good, and it is convenient for storage and transportation. It is very suitable for preparation as a raw material for pharmaceutical preparations.

Experimental Example 5, Humidity

The wettability test was carried out according to the Guiding Principles for Drug Hygroscopicity Test (Chinese Pharmacopoeia 2010 Edition Part II Appendix XIX J). Take a dry stuffed glass weighing bottle (outer diameter 50mm, height 15mm), placed in a suitable 25 ° C ± 1 ° C constant temperature dryer (lower ammonium chloride saturated solution) on the day before the test, accurately weighed Weight (m1); suitable for the crystal form of the present invention The amount is laid flat in the above weighing bottle. The thickness of the test sample is generally about 1 mm, and the weight is accurately weighed (m2); the weighing bottle is opened and placed under the above constant temperature and humidity conditions with the bottle cap. 24 hours; cover the weighing bottle cap and accurately weigh (m3).

The criteria for judging the wettability test are as follows:

Deliquescence: absorbs enough water to form a liquid

Extremely easy to wettability: X% ≥ 15%;

Hygroscopicity: 2% ≤ X% < 15%;

Slightly hygroscopic: 0.2% ≤ X% < 2%;

No or almost no hygroscopicity: X% < 0.2%.

According to the above method, the (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethyl group of the present invention was measured. The weight gain percentage of the phosphinyloxy-4-yl]pyridin-2-amine crystal form compound was 0.02%, indicating that the crystal form of the present invention has no hygroscopicity and is hardly deliquescent under the influence of high humidity.

Experimental Example 6, Solubility

According to the Chinese Pharmacopoeia 2010 edition of the second part of the test. Weigh the crystal form of the invention into a fine powder, place it in a solvent of a certain capacity at 25 ° C ± 2 ° C, and shake vigorously for 30 seconds every 5 minutes; observe the dissolution within 30 minutes, if no solute particles are visible, It is considered to be completely dissolved. The results are shown in Table 5.

table 5

Solvent Sample weight (g) Solvent usage (ml) Dissolution in conclusion Methanol 0.1 0.2 completely dissolved Soluble acetone 0.1 4.0 completely dissolved Slightly soluble 0.1mol/L hydrochloric acid 0.1 2.4 completely dissolved Dissolve

As apparent from Table 5, (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethyl group of the present invention The phosphonooxy-4-yl]pyridin-2-amine crystalline form compound has high solubility, indicating its high bioavailability.

Claims (10)

a crystalline form of the compound of formula I, characterized in that the crystalline form XRPD pattern exhibits a diffraction peak at 2θ (±0.2°) of 6.63, 7.64, 10.38, 11.38, 12.07, 13.23, 15.48, 16.90,

The crystal form according to claim 1, wherein the crystal form XRPD pattern further exhibits a diffraction peak at 2θ (±0.2°) of 19.47, 20.06, 20.83, 22.43, 24.26, 26.18, 29.74. The crystalline form according to claim 1 wherein said crystalline XRPD pattern is as shown in FIG. A process for the preparation of a crystalline form according to any one of claims 1 to 3 which comprises dissolving a compound of the formula I with an organic solvent, cooling and crystallization by stirring, and filtering to obtain a target crystalline form. A process for the preparation of a crystalline form according to any one of claims 1 to 3, which comprises dissolving a compound of the formula I in an organic solvent, adding an anti-solvent to agitate the crystal, and filtering to obtain a target crystalline form. The preparation method according to any one of claims 4 or 5, further comprising a drying step after filtration, preferably, the drying temperature is 20 ° C or higher, preferably 70 ° C or higher, more preferably 80 ° C or higher. The preparation method according to any one of claims 4 to 5, wherein the organic solvent is selected from the group consisting of acetonitrile, ethyl acetate and/or butyl acetate. The preparation method according to claim 5, wherein the anti-solvent is selected From isopropyl ether, n-heptane and/or n-hexane. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of any of claims 1-3 and a pharmaceutically acceptable carrier. Use of the crystalline form according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 9 for the preparation of an antitumor drug. Preferably, the tumor is lung cancer.

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