WO2014183665A1

WO2014183665A1 - Oxazolidinone derivative crystal form i and preparation method and use thereof

Info

Publication number: WO2014183665A1
Application number: PCT/CN2014/077666
Authority: WO
Inventors: 黄长江; 袁静; 商倩; 刘鹏; 王成港; 付晓丽; 刘欢; 张士俊; 靳文仙; 徐为人
Original assignee: 天津药物研究院
Priority date: 2013-05-17
Filing date: 2014-05-16
Publication date: 2014-11-20
Also published as: CN103242307A; CN103242307B

Abstract

Provided is the crystal form I of (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridine-1-yl)phenyl)-1,3-oxazolidine-5-yl)methyl)thiophene-2-formamide, and preparation method and use thereof. The prepared crystal form I of (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridine-1-yl)phenyl)-1,3-oxazolidine-5-yl)methyl)thiophene-2-formamide is characterised by an X-ray powder diffractogram.

Description

Oxazolone derivative crystal form I and preparation method and use thereof

The invention belongs to the technical field of medicine, relates to an oxazolidinone derivative crystal form I and a preparation method and use thereof, and more particularly to a (S)-5-chloro-N-((2- Crystal form of oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide I and its preparation method and use. Background technique

Thrombosis is an abnormal coagulation of blood in a flowing state due to activation of platelets and activation of blood coagulation factors.

Blood coagulation is originally a protective mechanism of organisms. There are antagonistic coagulation systems and anticoagulant systems in the blood. Their dynamic balance ensures the potential coagulability of blood and always ensures the fluid state of blood. .

However, sometimes under certain factors that promote the blood coagulation process, the above-mentioned dynamic balance is broken, triggering the blood coagulation process, and the blood can form a thrombus or embolism, leading to thrombosis such as myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism, etc. Embolism disease. Thromboembolic disease is the most serious disease in cardiovascular disease and the first killer of human health. In China, with the improvement of living standards and the aging of the population, the incidence, mortality and disability of these diseases have increased year by year.

Existing antithrombotic diseases are classified into antiplatelet drugs, anticoagulant drugs, and fibrinolytic drugs. Among them, anticoagulant drugs are the main content of antithrombotic therapy. Recent studies have shown that Xa is the best target for the development of new anticoagulant drugs. The coagulation process is usually divided into an endogenous coagulation pathway and an exogenous coagulation pathway. Many blood coagulation factors are involved in the coagulation process, and each inactive factor converts the next inactive coagulation factor precursor into an activated form. The final summary of the endogenous and exogenous pathways is the conversion of factor X to Xa. Therefore, in theory, direct inhibition of factor Xa activity should result in highly effective anticoagulant effects without the side effects of thrombin inhibitors. Because it directly inhibits the activity of factor Xa, it has the least effect on the normal hemostatic reaction/regulation process. For example, platelets remain capable of responding to low levels of catalytically active thrombin and thus do not affect platelet thrombosis and minimize the risk of hemorrhagic syndrome.

Patent CN201110337461.4 provides a novel compound having the structure of formula (I), which is a low molecular weight orally administrable inhibitor of factor Xa, which can be used for preventing/treating diseases, preferably thromboembolic diseases and/or thrombosis. Embolism complications, especially deep vein thrombosis, pulmonary embolism, heart Muscle infarction and so on.

Formula (I) Chemical structure of the compound:

( " ) Chemical Name:

(S)- ⁵ -Chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine _ ⁵ _ Base) methyl) thiophene-2-carboxamide.

Meanwhile, the applicant's prior patent CN201110337461.4 describes the preparation of the compound of formula (I).

However, this patent does not relate to the crystalline form of the compound of formula (I). In view of the pharmaceutical value of the compound, it is necessary to obtain a high purity, defined crystal form. Summary of the invention

An object of the present invention is to provide (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3 Form I of -oxazolidine-5-yl)methyl)thiophene-2-carboxamide.

Measured by D/Max-2500 X-ray diffractometer, the measurement conditions were: CuKa, 40KV, 100 mA, and the X-ray powder diffraction characteristic absorption peak (2 θ ) values of the crystal form were: 4.04, 8.08, 12.16, 13.96, 17.14, 19.40, 19.76, 20.30, 23.80, 24.46, 28.60, 32.26; 2 Θ Measurement error is ± 0.2.

The crystal form X-ray powder diffraction has a diffraction angle (2 Θ ) and a crystal plane spacing (d value) as shown in Table 1, and the measurement error of 2 Θ is ± 0.2. Table 1 Crystalline X-ray powder diffraction diffraction angle and interplanar spacing

(S)_ ⁵ _Chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine _ ⁵ _ Form I of methyl)thiophene-2-carboxamide, having X-ray powder diffraction having the characteristic absorption (S) ^-5 -chloro-N-((2-oxo-3-) as shown in Figure 1. Form I of (4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine- ⁵ -yl)methyl)thiophene-2-carboxamide, the melting point of which is 227.6~228.1 °C.

Another object of the present invention is to provide (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1, Process for the preparation of Form I of 3-oxazolidine-5-yl)methyl)thiophene-2-carboxamide.

The present invention provides (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazole Process for the preparation of crystalline form I of alk-5-yl)methyl)thiophene-2-carboxamide, which comprises (S) ^-5 -chloro-N-((2-oxo-3-(4-) (2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine- ⁵ -yl)methyl)thiophene-2-carboxamide crystallized in a crystallization solvent, wherein the crystallization The solvent is a mixed solution of an aqueous solution of formic acid and ethanol.

Specifically, the preparation method may include: (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-) Pyridin-1-yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide is added to the mixed solution, dissolved by stirring and heated to room temperature to precipitate crystals. Filtration and drying gave (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3- Form I of oxazolidine-5-yl)methyl)thiophene-2-carboxamide.

The mixed solution is composed of a formic acid aqueous solution having a concentration of 80% to 95% and ethanol in a volume ratio of 1:0.5 to 1.5. Preferably, the mixed solution is composed of a formic acid aqueous solution having a concentration of 85% to 90% and ethanol in a volume ratio of 1: 0.8 to 1.2. Most preferably, the mixed solution consists of a concentration of 88% aqueous formic acid and ethanol in a volume ratio of 1:1.

Preferably, the mixed solution is used in an amount of: the total volume of the mixed solution is the corresponding (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridine)- 15- to ⁶ -phenyl)-1,3-oxazolidine- ⁵ -yl)methyl)thiophene-2-carboxamide 15 to 25 times the mass, the multiple is the volume-to-mass ratio, the unit is mL/g .

Still another object of the present invention is to provide (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3 Use of Form I of oxazolidine-5-yl)methyl)thiophene-2-carboxamide for the preparation of a medicament for preventing/treating a thromboembolic disease and/or thromboembolic complications and for preventing/treating thromboembolism Use in sexually transmitted diseases and/or thromboembolic complications.

The present invention provides the (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3 Use of Form I of oxazolidine-5-yl)methyl)thiophene-2-carboxamide for the manufacture of a medicament for the prevention/treatment of thromboembolic disorders and/or thromboembolic complications.

The present invention also provides the (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1, Use of Form I of 3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide for the prevention/treatment of thromboembolic disorders and/or thromboembolic complications.

Within the scope of the present invention, "thromboembolic disease" includes, inter alia, diseases such as myocardial infarction with ST-segment elevation (STEMI) and without ST-segment elevation (without STEMI), stable/unstable angina, coronary interventional therapy For example, re-occlusion and restenosis after angioplasty or aortic coronary artery bypass surgery, peripheral vascular occlusive disease, pulmonary embolism, deep vein thrombosis and renal vein thrombosis, transient ischemic attack, and thrombosis and thrombosis Embolism type stroke.

The thromboembolic disease also includes cardiac thromboembolism, such as stroke, cerebral ischemia, systemic thromboembolism, and ischemia, and also, for example, acute, intermittent or persistent cardiac arrhythmia, cardioversion, valvular heart disease or Artificial heart valve.

The thromboembolic diseases also include atherosclerotic vascular diseases and inflammatory diseases (such as motor system rheumatic diseases), as well as other diseases (such as diabetes, tumor diseases, especially major surgical intervention or radiotherapy/chemotherapy). The patient caused by thromboembolism. The thromboembolic disease also includes diffuse invasive coagulation (DIC).

The thromboembolic complications include microvascular hemolytic anemia, complications such as hemodialysis and heart valve repair in the context of extracorporeal blood circulation.

(S)-5-Chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine- Form I of 5-yl)methyl)thiophene-2-carboxamide can also be used to prevent coagulation in vitro. For example, it is used to store blood and plasma, and biological samples containing factor Xa.

(S)-5-Chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine of the invention Form I of -5-yl)methyl)thiophene-2-carboxamide is effective over a relatively wide range of measurements, for example, a daily dose of from 1 to 1000 mg per person, which may be administered once or several times. medicine. The actual dose should be determined by the doctor according to the relevant circumstances, including the physical condition of the subject, the route of administration, age, weight, individual response to the drug and the severity of the symptoms. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine X-ray powder diffraction pattern of Form I of -5-yl)methyl)thiophene-2-carboxamide. The best way to implement the invention

The invention is further illustrated by the following examples, which are merely illustrative and are not intended to limit the scope of the invention in any way. Example 1

(S)- ⁵ -Chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine _ ⁵ _ Preparation of methyl)thiophene-2-carboxamide

The preparation of the compound of the formula (I) is described in the patent CN201110337461.4. Example 2

(S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazole of Form I Preparation of alk-5-yl)methyl)thiophene-2-carboxamide

Weigh 10 g of (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazole Alkan-5-yl)methyl)thiophene-2-carboxamide, added 150mL mixed solution (88% formic acid: ethanol = 1:1, V: V), heated to reflux, stirred and dissolved, stirred to room temperature, kept warm and stirred After 2 hours, filtration and drying, 8 g of white solid was obtained as (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridine-1) -base) Phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide. Example 3

Weigh 20g of (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazole Alk-5-yl)methyl)thiophene-2-carboxamide, adding 160 mL of 88% formic acid, 160 mL of ethanol, refluxing under reflux, stirring and stirring, cooling to room temperature with a water bath, crystallizing, stirring for 1 hour, filtration, ethanol Wash (120 mL x 4 ), dry at room temperature for 12 hours, and dry at 80 ° C for 4 hours to obtain 15.6 g of white solid. (S)-5-chloro-N-((2-oxo-3-) 4-(2-Oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide, MP: 227.6~228.1 °C. Example 4

Weigh 15g of (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazole Alkan-5-yl)methyl)thiophene-2-carboxamide, adding 375 mL of mixed solution (88% formic acid: ethanol = 1: 1, V: V), refluxing at elevated temperature, stirring and dissolving, adding activated carbon, stirring for 10 minutes with heat Filtration, filtration, 15 ° C water bath stirring to room temperature, stirring for 3 hours, filtration, ethanol rinse (90mL x 4), drying at room temperature for 12 hours, drying at 80 ° C for 4 hours, to obtain a white solid 10.5g, crystal (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine of type I _ ⁵ _ yl) methyl) thiophene-2-carboxamide. Example 5

(S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazole of Form I Stability test of alk-5-yl)methyl)thiophene-2-carboxamide

(S)-5-Chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine-5 The stability of the crystal form I of methyl-thiophene-2-carboxamide was investigated. The stability at high temperature (60 ° C:), high humidity (92.5%), and illumination (4500 Lx) was investigated. The test results are shown in Table 2. Table 2 Stability test results

Tests have shown that under high temperature, high humidity and light conditions, the maximum impurities and total impurities within 10 days have not increased significantly, and the chemical stability is good.

Claims

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1. (S)-5-Chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazole Form I of alk-5-yl)methyl)thiophene-2-carboxamide characterized by a characteristic absorption peak (2 Θ ) of the X-ray powder diffraction pattern of the crystalline form: 4.04, 8.08, 12.16, 13.96, 17.14, 19.40, 19.76, 20.30, 23.80, 24.46, 28.60, 32.26; 2 Θ Measurement error is ± 0.2.

2. (S)-5-Chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-) according to claim 1 Form I of 3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide, wherein the X-ray powder diffraction pattern of the crystalline form has a characteristic absorption peak as shown in FIG.

3. (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1, according to claim 1 Process for the preparation of Form I of 3-oxazolidine-5-yl)methyl)thiophene-2-carboxamide comprising the step of (S) ^-5 -chloro-N-((2-oxo-3-) (4-(2-Oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine- ⁵ -yl)methyl)thiophene-2-carboxamide crystallized in a crystallization solvent, characterized The crystal solvent is a mixed solution of an aqueous solution of formic acid and ethanol.

The process according to claim 3, which comprises: (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridine-1) -yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide is added to a mixed solution of aqueous formic acid and ethanol, dissolved by stirring and heated to room temperature to precipitate crystals. Filtration to obtain the (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3- Form I of oxazolidine-5-yl)methyl)thiophene-2-carboxamide.

The preparation method according to claim 3 or 4, wherein the mixed solution is composed of a formic acid aqueous solution having a concentration of 80% to 95% and ethanol in a volume ratio of 1:0.5 to 1.5.

The preparation method according to claim 5, wherein the mixed solution is composed of an aqueous solution of formic acid having a concentration of 85% to 90% and ethanol in a volume ratio of 1:0.8 to 1.2, and most preferably, the mixed solution is composed of An aqueous solution of formic acid having a concentration of 88% and ethanol were composed in a volume ratio of 1:1.

The production method according to claim 3 or 4, wherein the total volume of the mixed solution is the corresponding (S) ^-5 -chloro-N-((2-oxo-3-(4-(2-oxo)) -2H-pyridin-1-yl)phenyl)-1,3-oxazolidine- ⁵ -yl)methyl) The mass of thiophene-2-carboxamide is 15 to 25 times, and the multiple is a volume-to-mass ratio in units of mL/g.

8. (S)-5-Chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)) according to claim 1 or 2 Use of Form I of 1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide for the manufacture of a medicament for the prevention/treatment of thromboembolic disorders and/or thromboembolic complications.

9. (S)-5-Chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)) according to claim 1 or 2 Use of Form I of 1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide for the prevention/treatment of thromboembolic disorders and/or thromboembolic complications.