WO2014183667A1

WO2014183667A1 - Acetic acid solvate of oxazolidinone derivative, preparation method for the solvate, and application thereof

Info

Publication number: WO2014183667A1
Application number: PCT/CN2014/077668
Authority: WO
Inventors: 黄长江; 袁静; 付晓丽; 张士俊; 商倩; 刘旭圆; 刘登科; 徐为人; 汤立达
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: CN104163819A

Abstract

Provided is an acetic acid solvate of (S)-5-chlorine-N-((2-oxo-3-(4-(2-oxo-2H-pyrid-1-yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide, a preparation method for the solvate, and an application thereof. The prepared acetic acid solvate of (S)-5-chlorine-N-((2-oxo-3-(4-(2-oxo-2H-pyrid-1-yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide is characterized via an X-power diffraction diagram.

Description

Acetic acid solvate of oxazolidinone derivative, preparation method and use thereof

The invention belongs to the technical field of medicine, and relates to an acetic acid solvate of an oxazolidinone derivative, a preparation method thereof and use thereof, in particular, the invention relates to (S)-5-chloro-N-((2- Acetic acid solvent of oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide 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 (A), 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.

The chemical structure of the compound of formula (A):

(A)

Methyl)thiophene-2-carboxamide.

In the meantime, the applicant's prior patent CN201110337461.4 describes the preparation method of the formula (A):

A

Summary of the invention

An object of the present invention is to provide (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridyl)phenyl)-1,3-oxazole Acetic acid solvate of 垸-5-yl)methyl)thiophene-2-carboxamide, represented by the chemical formula (I):

Wherein n is selected from the group consisting of 0.5 to 1.5, such as 0.5, 0.6, 07, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 and 1.5; preferably 0.5 1.2, most preferably 0.8.

The measurement conditions were as follows: CuKa, 40 KV, 100 mA, and the solvate X-ray powder diffraction characteristic absorption peak (2 Θ ) value was 3.60, 7.04, 10.50, 14.00, measured by D/Max-2500 X-ray diffractometer. 17.48, 20.12, 21.00, 23.86, 24.56, 26.42, 28.12; 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 results

(S)_ ⁵ _Chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine _ ⁵ _ Acetic acid solvate of methyl)thiophene-2-carboxamide having X-ray powder diffraction having a characteristic absorption peak as shown in FIG.

In one embodiment, the invention (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1) The differential thermal analysis of the acetic acid solvate of 3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide is shown in Figure 2. The test results show that the solvate has an endotherm at 155 °C. And with about 10% weight loss, it was proved that the solvate crystal form contained about 10% by weight of acetic acid. 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 acetic acid solvates of 3-oxazolidin-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 an acetic acid solvate 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-oxazolidin-5-yl)methyl)thiophene-2-carboxamide crystallized in a crystallization solvent, wherein the crystallization The solvent is acetic acid.

Specifically, the preparation method may include: (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)) -1,3-oxazolidine-5-yl)methyl)thiophene-2-carboxamide is added to acetic acid, dissolved by heating, allowed to stand for crystallisation, filtered and dried to give (S)-5-chloro-N- ((2-Oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine-5-yl)methyl)thiophene-2-methyl Acetate solvate of amide.

Preferably, the amount of the crystallization solvent is as follows: The volume of acetic acid is the corresponding (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridine-1-) 10) to 10 times, preferably 25 to 40 times the mass of the phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide, the multiple being a volume-to-mass ratio, The unit is mL/g.

The heating and dissolving temperature may be from 80 ° C to reflux temperature, preferably from 80 to 110 ° C.

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 an acetic acid solvate of oxazolidine-5-yl)methyl)thiophene-2-carboxamide for the preparation of a medicament for preventing/treating a thromboembolic disease and/or a thromboembolic complication and for preventing/treating a thrombus Use in embolic disease 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 an acetic acid solvate of oxazolidine-5-yl)methyl)thiophene-2-carboxamide for the preparation 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)-1,3 Use of an acetic acid solvate of -oxazolidin-5-yl)methyl)thiophene-2-carboxamide for the prevention/treatment of thromboembolic diseases 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, Heart valve 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- The acetic acid solvate of 5-yl)methyl)thiophene-2-carboxamide can also be used to prevent coagulation in vitro. For example, it is used to preserve 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 The acetic acid solvate 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 can 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-^-2H-pyridine-1-yl)phenyl)-1,3-oxazolidine- Acetic acid solvated 4 X-ray powder diffraction pattern of 5-yl)methyl)thiophene-2-carboxamide;

Figure 2 is (S)-5-chloro-indole-((2-oxo-3-(4-(2-^-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine- Ei' differential thermal analysis 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 formula (A) is described in patent CN201110337461.4. Example 2

(S)_ ⁵ _Chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine _ ⁵ _ Preparation of acetic acid solvate of 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 Alkyl-5-yl)methyl)thiophene-2-carboxamide, added with 250 mL of acetic acid, refluxed at elevated temperature, stirred and dissolved, allowed to stand at 45 ° C for 6 hours, allowed to stand at room temperature for 6 hours, filtered, and washed with ethanol. (50mL x 4 ), dried at room temperature for 12 hours, and dried at 50 ° C for 4 hours to obtain (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridine) Acetic acid solvate of -1-yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide. The X-powder diffraction pattern is shown in Figure 1. The differential thermal analysis is shown in Figure 2. The n value of the chemical structure is calculated to be 0.8. Example 3

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

Weigh 20g 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 600 mL of acetic acid, heated to 100 ° C, stirred and dissolved, added to activated carbon, kept under stirring for 10 minutes, incubated with heat, and the filtrate was allowed to stand at 40 ° C for 16 H, filtered, ethanol rinse (80 mL x 4 ), dried to give 13.6 g (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridine)- Acetic acid solvate of 1-yl)phenyl)-1,3-oxazolidine- ⁵ -yl)methyl)thiophene-2-carboxamide. Its X-powder diffraction pattern is shown in Figure 1, and its differential thermal analysis shows n = 1. Example 4

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 800 mL of acetic acid, heating to 80 ° C, stirring and dissolving, standing at 45 ° C for 8 hours, standing at room temperature for 8 hours, and filtering. Rinse with ethanol and dry to give (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3 Acetic acid solvate of -oxazolidine- ⁵ -yl)methyl)thiophene-2-carboxamide. Its X-powder diffraction pattern is shown in Figure 1, and its differential thermal analysis shows n = 1.2. Example 5 (S)_ ⁵ _Chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine _ ⁵ _ Preparation of acetic acid solvate of methyl)thiophene-2-carboxamide

Weigh 15g 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 525 mL of acetic acid, refluxing at elevated temperature, stirring and dissolving, incubated at room temperature, standing at 40 ° C for 8 hours, filtering, ethanol washing, drying, and obtaining 11.5 g (S)-5-Chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine _ ⁵ Acetic acid solvate of _yl)methyl)thiophene-2-carboxamide. Its X-powder diffraction pattern is shown in Figure 1. Example 6

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 200 mL of acetic acid, heating to 100 ° C, stirring and dissolving, adding activated carbon, stirring for 10 minutes with heat, filtering with heat, cooling the filtrate rapidly, stirring at 10 ° C Crystals for 4 hours, filtered, washed with ethanol (80 mL X 4 ) and dried to give 13.6 g of (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-) Acetic acid solvate of pyridin-1-yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide. Its X-powder diffraction pattern is shown in Figure 1, and its differential thermal analysis shows n = 0.5.

Claims

profit requirements

1. A (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl))-1,3-oxazole The acetic acid solvate of alkyl-5-yl)methyl)thi-2-carboxamide has a chemical formula as shown in formula (I):

Among them, n is selected from 0.5~1.5. 2. (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1 as claimed in claim 1 ,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide acetic acid solvate, where n is 0.5-1.

2, preferably 0.8.

3. (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl) as claimed in claim 1 or 2) -The acetic acid solvate of -1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide has a characteristic absorption peak (2Θ) value of its X-ray powder diffraction spectrum: 3.60, 7.04, 10.50, 14.00, 17.48, 20.12, 21.00, 23.86, 24.56, 26.42, 28.12; 2 Θ measurement error is ± 0.2.

4. (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl) as claimed in any one of claims 1 to 3 The acetic acid solvate of )phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide has a characteristic absorption peak as shown in Figure 1 in its X-ray powder diffraction spectrum.

5. (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)) according to any one of claims 1 to 4) A method for preparing the acetic acid solvate of phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide, which method includes adding (S) ^-5 -chloro-N-((2 -Oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide in crystallization Crystallization in a solvent is characterized in that: the crystallization solvent is acetic acid.

6. The preparation method as claimed in claim 5, the method comprising: (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridine-1) -(yl)phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide added into acetic acid, heated to dissolve, cooled to crystallize, filtered, and dried to obtain the (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridine- 1-yl)phenyl)-1,3-oxazolidin-5-yl)methyl)ethyl)thiophene-2-carboxamide

7. The preparation method as claimed in claim 5 or 6, wherein the volume of the acetic acid is corresponding

(S) ^-5 -Chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)phenyl)-1,3-oxazolidine_ ⁵ _ (methyl)methyl) thiophene-2-carboxamide is 10 to 40 times the mass, preferably 25 to 40 times, and the multiple is the volume-mass ratio, and its unit is mL/g.

8. The preparation method as claimed in claim 6, wherein the temperature for heating and dissolving is 80°C ~ reflux temperature, preferably 80~110°C.

9. (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)) according to any one of claims 1 to 4) Acetic acid solvate of phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide in the preparation of drugs for preventing/treating thromboembolic diseases and/or thromboembolic complications use.

10. (S)-5-chloro-N-((2-oxo-3-(4-(2-oxo-2H-pyridin-1-yl)) according to any one of claims 1 to 4 Use of the acetic acid solvate of phenyl)-1,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide in the prevention/treatment of thromboembolic diseases and/or thromboembolic complications.