CN102838617A - Polymorph and pharmaceutical composition of (S)-2-(2- nicotinoyloxyjatropha-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2-(2-chlorphenyl)-methyl acetate - Google Patents
Polymorph and pharmaceutical composition of (S)-2-(2- nicotinoyloxyjatropha-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2-(2-chlorphenyl)-methyl acetate Download PDFInfo
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- CN102838617A CN102838617A CN201110167220XA CN201110167220A CN102838617A CN 102838617 A CN102838617 A CN 102838617A CN 201110167220X A CN201110167220X A CN 201110167220XA CN 201110167220 A CN201110167220 A CN 201110167220A CN 102838617 A CN102838617 A CN 102838617A
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- methyl acetate
- thiophene
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Abstract
The invention discloses a polymorph of (S)-2-(2- nicotinoyloxyjatropha-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2-(2-chlorphenyl)-methyl acetate and a preparation method and medical applications thereof. A pharmaceutical composition containing the compound disclosed in the invention can be used for preparing medicines for preventing or treating thrombus and thrombotic diseases.
Description
Technical field
The present invention relates to the crystal formation of medical compounds; Be specifically related to a kind of (S)-2-(2-(nicotinylsalicylic oxygen)-6; 7-dihydro-thiophene also [3; 2-c] polymorphic form of pyridine-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate, in addition, the invention also discloses the preparation method and the pharmaceutical composition thereof of this crystal formation thing.
Background technology
The cardiovascular and cerebrovascular thrombotic diseases is a kind of common disease, is that master's the sickness rate of thrombotic disease is in rising trend with crown thrombus and cerebral thrombosis in recent years, and the serious harm human beings'health is therefore, very important to the study on prevention of this type disease.Platelet aggregation is a key link in the normal clotting mechanism, but hematoblastic to stick, assemble also be thrombotic initial link.Therefore, the anticoagulant medicine is being brought into play important effect in the treatment thrombus disease, and the anti-platelet aggregation medicine is the focus that people study always.
The inventor has described in one Chinese patent application 201010104091.5 and 201010624329.7 and has comprised (S)-2-(2-(nicotinylsalicylic oxygen)-6; 7-dihydro-thiophene also [3; 2-c] pyridine-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate has novel 2-hydroxy tetrahydro thienopyridine derivative of anti-platelet aggregation effect and preparation method thereof at interior one type, but above-mentioned patented claim is not described the preparation and the sign of the polymorphic form of title compound free alkali.
The crystal formation of material is the form of material existence, and will inevitably there be different crystal formations in medicine as the material of treatment disease.The crystal formation of medicine can influence the physico-chemical property of material, comprises fusing point, chemicalstability, apparent solubility, dissolution rate, optics and mechanical properties, vp and density.These character can directly influence the processing or the production of bulk drug and preparation, and can influence stability of formulation, solubleness and bioavailability.Therefore, the medicine crystal formation must be the important content of drug research, detection and supervision, also is the important content of drug quality control.
Summary of the invention
(2-(nicotinylsalicylic oxygen)-6,7-dihydro-thiophene be a kind of polymorphic form of [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate (compound shown by formula I) also to the invention provides (S)-2-.
Another object of the present invention provides a kind of preparation method of formula I compound polymorphic form.
The 3rd purpose of the present invention provides the medicinal compsns that contains above-mentioned formula I compound polymorphic form.
Specifically, the invention provides a kind of polymorphic form A that is substantially free of the formula I compound of other solvents.
The polymorphic form A of formula I compound provided by the present invention; Use the Cu-Ka radiation; Its typical X-x ray diffration pattern x; 2 θ that show with kilsyth basalt have diffraction peak 13.4 ± 0.2,16.1 ± 0.2,18.6 ± 0.2,18.9 ± 0.2 and 19.5 ± 0.2; Particularly; 4.0 ± 0.2,8.5 ± 0.2,9.6 ± 0.2,12.1 ± 0.2,12.5 ± 0.2,14.5 ± 0.2,15.5 ± 0.2,16.6 ± 0.2,20.2 ± 0.2,20.9 ± 0.2,21.6 ± 0.2,21.9 ± 0.2,22.5 ± 0.2,22.8 ± 0.2,23.3 ± 0.2,23.6 ± 0.2,23.9 ± 0.2,24.2 ± 0.2,24.6 ± 0.2,25.1 ± 0.2,25.3 ± 0.2,26.2 ± 0.2,27.3 ± 0.2,27.8 ± 0.2,28.5 ± 0.2,29.4 ± 0.2 one or more (with arbitrary combination, comprising more than two, perhaps whole) diffraction peak is arranged; Especially, at 4.0 ± 0.2,8.5 ± 0.2,9.6 ± 0.2,12.1 ± 0.2,12.5 ± 0.2,13.4 ± 0.2,14.5 ± 0.2,15.5 ± 0.2,16.1 ± 0.2,16.6 ± 0.2,18.6 ± 0.2,18.9 ± 0.2,19.5 ± 0.2,20.2 ± 0.2,20.9 ± 0.2,21.6 ± 0.2,21.9 ± 0.2,22.5 ± 0.2,22.8 ± 0.2,23.3 ± 0.2,23.6 ± 0.2,23.9 ± 0.2,24.2 ± 0.2,24.6 ± 0.2,25.1 ± 0.2,25.3 ± 0.2,26.2 ± 0.2,27.3 ± 0.2,27.8 ± 0.2,28.5 ± 0.2,29.4 ± 0.2 places diffraction peak is arranged.
The polymorphic form A of formula I compound:
In addition, the polymorphic form A of formula I compound of the present invention is characterized by at about 3005cm with the infrared absorption pattern that the KBr compressing tablet records
-1, 2989cm
-1, 2952cm
-1, 1738cm
-1, 1684cm
-1, 1590cm
-1, 1435cm
-1, 1275cm
-1, 1260cm
-1, 1203cm
-1, 766cm
-1, 754cm
-1, 702cm
-1There is absorption peak at the place.
The polymorphic form A of formula I compound provided by the present invention, the maximum endothermic transition of its DSC scanning be about 90 ℃ to 110 ℃, preferably, and about 95 ℃ or 98 ℃.
In embodiments of the invention, the invention provides the preparation method of the polymorphic form A of formula I compound, comprise the steps:
(1) (2-(nicotinylsalicylic oxygen)-6,7-dihydro-thiophene also [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate are dissolved in a kind of solubility organic solvent, again with getting oily matter after the solvent evaporated under reduced pressure with (S)-2-;
(2) add another kind of organic solvent in the oily matter that in step (1), obtains, after stirring or supersound process, separate out solid;
(3) reclaim solid, drying under reduced pressure.
In above-mentioned steps (1), the organic solvent that is adopted is selected from a kind of solvent or the two or more mixed solvents in acetone, methylene dichloride, ETHYLE ACETATE, methyl acetate, n-butyl acetate, acetonitrile, toluene or the THF.
In above-mentioned steps (2), the organic solvent that is adopted is selected from a kind of solvent or the two or more mixed solvents in ethanol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, sec-butyl alcohol, terepthaloyl moietie, ether, isopropyl ether, MTBE, sherwood oil, normal hexane, Skellysolve A or the hexanaphthene.
The present invention also provides the pharmaceutical composition of a kind of prevention or treatment thrombus and embolism relative disease; Wherein contain (S)-2-(2-(nicotinylsalicylic oxygen)-6 that treats significant quantity; The 7-dihydro-thiophene also the polymorphic form A of [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate as active ingredient and pharmaceutically acceptable carrier.Said pharmaceutical composition can be a dosage form conventional on the technology of pharmaceutics such as conventional tablet or capsule, slow releasing tablet or capsule, controlled release tablet or capsule, granule, powder, syrup, oral liquid, injection.
Description of drawings
Fig. 1 is that (2-(nicotinylsalicylic oxygen)-6,7-dihydro-thiophene be the exemplary x-ray diffracting spectrum of the polymorphic form A of [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate also for (S)-2-;
Fig. 2 is that (2-(nicotinylsalicylic oxygen)-6,7-dihydro-thiophene be the IR infrared absorpting light spectra of the polymorphic form A of [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate also for (S)-2-;
Fig. 3 is that (2-(nicotinylsalicylic oxygen)-6,7-dihydro-thiophene be the DSC scintigram of the polymorphic form A of [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate also for (S)-2-;
Fig. 4 is that (2-(nicotinylsalicylic oxygen)-6,7-dihydro-thiophene be the TGA scintigram of the polymorphic form A of [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate also for (S)-2-.
Embodiment
Specify content of the present invention through embodiment below.In the present invention, the embodiment of the following stated is in order better to set forth the present invention, is not to be used for limiting scope of the present invention.
(2-(nicotinylsalicylic oxygen)-6,7-dihydro-thiophene also [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate (2.20g) are dissolved in the acetone, remove acetone again under reduced pressure and get colorless oil with (S)-2-.At room temperature, in this oily matter, add 10mL ethanol, under fully stirring, have solid to separate out, continue static crystallization under 3 ℃.The filtering solvent gets filter cake.Filter cake drying under reduced pressure under room temperature gets solid 1.78g, fusing point: 95～97 ℃.This solid is that (2-(nicotinylsalicylic oxygen)-6,7-dihydro-thiophene be the polymorphic form A of [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate also for (S)-2-through X-ray powder diffraction, infrared scan, DSC scanning, TGA scanning conclusive evidence.
(2-(nicotinylsalicylic oxygen)-6,7-dihydro-thiophene also [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate (1.10g) are dissolved in the ETHYLE ACETATE, remove acetone again under reduced pressure and get colorless oil with (S)-2-.At room temperature, in this oily matter, add 10mL ethanol, under fully stirring, have solid to separate out, continue static crystallization under 3 ℃.The filtering solvent gets filter cake.Filter cake drying under reduced pressure under room temperature gets solid 0.75g, fusing point: 95～97 ℃.(2-(nicotinylsalicylic oxygen)-6,7-dihydro-thiophene be the polymorphic form A of [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate also for (S)-2-through the X-ray powder diffraction conclusive evidence for this solid.
(2-(nicotinylsalicylic oxygen)-6,7-dihydro-thiophene also [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate (1.02g) are dissolved in the acetone, and steaming removes acetone and gets colorless oil again with (S)-2-.At room temperature, in this oily matter, add the 10mL MTBE, be statically placed in after the supersound process under the room temperature in 3 ℃ of environment, have solid to separate out.The filtering solvent gets filter cake.Filter cake drying under reduced pressure under room temperature gets pulverulent solids 0.71g, fusing point: 95～97 ℃.(2-(nicotinylsalicylic oxygen)-6,7-dihydro-thiophene be the polymorphic form A of [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate also for (S)-2-through the X-ray powder diffraction conclusive evidence for this solid.
(2-(nicotinylsalicylic oxygen)-6,7-dihydro-thiophene also [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate (1.0g) are dissolved in the acetone, and steaming removes acetone and gets colorless oil again with (S)-2-.At room temperature, in this oily matter, add the 7ml isopropyl ether, be statically placed in after the supersound process in the room temperature environment under the room temperature, separate out solid.The filtering solvent, drying under reduced pressure gets solid 0.70g under room temperature, fusing point: 96～98 ℃.(2-(nicotinylsalicylic oxygen)-6,7-dihydro-thiophene be the polymorphic form A of [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate also for (S)-2-through the X-ray powder diffraction conclusive evidence for this solid.
Embodiment 5
Tablet
With (the S)-2-that makes among the embodiment 1 (2-(nicotinylsalicylic oxygen)-6; 7-dihydro-thiophene also [3; 2-c] an amount of and Magnesium Stearate (1g) of the polymorphic form A (50g), HPMC E (150g), starch (200g), 30 POVIDONE K 30 BP/USP 30 of pyridine-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate mixes; Granulate compressing tablet.
Claims (8)
1. (S)-2-(2-(nicotinylsalicylic oxygen)-6; 7-dihydro-thiophene also [3; 2-c] the polymorphic form A of pyridine-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate; Use the Cu-Ka radiation, its x-ray diffraction pattern, 2 θ that show with kilsyth basalt have diffraction peak 13.4 ± 0.2,16.1 ± 0.2,18.6 ± 0.2,18.9 ± 0.2 and 19.5 ± 0.2.
2. (S)-2-according to claim 1 (2-(nicotinylsalicylic oxygen)-6; 7-dihydro-thiophene also [3; 2-c] the polymorphic form A of pyridine-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate; Its x-ray diffraction pattern, 2 θ that show with kilsyth basalt also have one or more diffraction peaks 4.0 ± 0.2,8.5 ± 0.2,9.6 ± 0.2,12.1 ± 0.2,12.5 ± 0.2,14.5 ± 0.2,15.5 ± 0.2,16.6 ± 0.2,20.2 ± 0.2,20.9 ± 0.2,21.6 ± 0.2,21.9 ± 0.2,22.5 ± 0.2,22.8 ± 0.2,23.3 ± 0.2,23.6 ± 0.2,23.9 ± 0.2,24.2 ± 0.2,24.6 ± 0.2,25.1 ± 0.2,25.3 ± 0.2,26.2 ± 0.2,27.3 ± 0.2,27.8 ± 0.2,28.5 ± 0.2,29.4 ± 0.2.
3. (S)-2-according to claim 1 and 2 (2-(nicotinylsalicylic oxygen)-6; The 7-dihydro-thiophene is the polymorphic form A of [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate also, and the maximum endothermic transition of its DSC scanning is about 90 ℃ to 110 ℃; Preferably, about 95 ℃ or 98 ℃.
4. (2-(nicotinylsalicylic oxygen)-6,7-dihydro-thiophene be the polymorphic form A of [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate also, with the infrared absorption pattern that the KBr compressing tablet records, it is characterized by at about 3005cm according to described (the S)-2-of claim 1～3
-1, 2989cm
-1, 2952cm
-1, 1738cm
-1, 1684cm
-1, 1590cm
-1, 1435cm
-1, 1275cm
-1, 1260cm
-1, 1203cm
-1, 766cm
-1, 754cm
-1, 702cm
-1There is absorption peak at the place.
5. (2-(nicotinylsalicylic oxygen)-6,7-dihydro-thiophene be the preparation method of the polymorphic form A of [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate also, comprises the steps: for described (the S)-2-of claim 1～4
(1) (2-(nicotinylsalicylic oxygen)-6,7-dihydro-thiophene also [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate are dissolved in a kind of solubility organic solvent, again with getting oily matter after the solvent evaporated under reduced pressure with (S)-2-;
(2) add another kind of organic solvent in the oily matter that in step (1), obtains, after stirring or supersound process, separate out solid;
(3) reclaim solid, drying under reduced pressure.
6. the preparation method of claim 5; It is characterized in that the organic solvent that in step (1), is adopted is selected from a kind of solvent or the two or more mixed solvents in acetone, methylene dichloride, ETHYLE ACETATE, methyl acetate, n-butyl acetate, acetonitrile, toluene or the THF; The organic solvent that in step (2), is adopted is selected from a kind of solvent or the two or more mixed solvents in ethanol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, sec-butyl alcohol, terepthaloyl moietie, ether, isopropyl ether, MTBE, sherwood oil, normal hexane, Skellysolve A or the hexanaphthene.
7. the pharmaceutical composition of a prevention or treatment thrombus and embolism relative disease; It is characterized in that; Contain (the 2-(nicotinylsalicylic oxygen)-6 of (S)-2-described in the claim 1～4 in the said pharmaceutical composition; The 7-dihydro-thiophene is the polymorphic form A and the pharmaceutically acceptable carrier of [3,2-c] pyridines-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate also.
8. pharmaceutical composition as claimed in claim 7 is characterized in that, said pharmaceutical composition is tablet, capsule, slow releasing tablet, granule, powder, syrup, oral liquid or injection.
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| CN201110167220XA CN102838617A (en) | 2011-06-21 | 2011-06-21 | Polymorph and pharmaceutical composition of (S)-2-(2- nicotinoyloxyjatropha-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2-(2-chlorphenyl)-methyl acetate |
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| CN201110167220XA CN102838617A (en) | 2011-06-21 | 2011-06-21 | Polymorph and pharmaceutical composition of (S)-2-(2- nicotinoyloxyjatropha-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-2-(2-chlorphenyl)-methyl acetate |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101343278A (en) * | 2007-12-11 | 2009-01-14 | 鲁南制药集团股份有限公司 | Preparation method for hydrogenated pyridine derivant and its salt |
| WO2009130289A1 (en) * | 2008-04-25 | 2009-10-29 | Sandoz Ag | HYDROGENSULFATE SALT OF 2-ACETOXY-5-(a-CYCLOPROPYLCARBONYL-2-FLUOROBENZYL)-4,5,6,7-TETRAHYDROTHIENO[3,2-c]PYRIDINE AND ITS PREPARATION |
| CN101591344A (en) * | 2008-05-27 | 2009-12-02 | 连云港恒邦医药科技有限公司 | A kind of antithrombotic compound, Preparation Method And The Use |
| CN102120744A (en) * | 2010-02-02 | 2011-07-13 | 江苏威凯尔医药科技有限公司 | Optical-activity 2-hydroxytetrahydrothienopyridine derivative, preparation method and application thereof in pharmacy |
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- 2011-06-21 CN CN201110167220XA patent/CN102838617A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101343278A (en) * | 2007-12-11 | 2009-01-14 | 鲁南制药集团股份有限公司 | Preparation method for hydrogenated pyridine derivant and its salt |
| WO2009130289A1 (en) * | 2008-04-25 | 2009-10-29 | Sandoz Ag | HYDROGENSULFATE SALT OF 2-ACETOXY-5-(a-CYCLOPROPYLCARBONYL-2-FLUOROBENZYL)-4,5,6,7-TETRAHYDROTHIENO[3,2-c]PYRIDINE AND ITS PREPARATION |
| CN101591344A (en) * | 2008-05-27 | 2009-12-02 | 连云港恒邦医药科技有限公司 | A kind of antithrombotic compound, Preparation Method And The Use |
| CN102120744A (en) * | 2010-02-02 | 2011-07-13 | 江苏威凯尔医药科技有限公司 | Optical-activity 2-hydroxytetrahydrothienopyridine derivative, preparation method and application thereof in pharmacy |
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Application publication date: 20121226 |