CN108912142A - Pyrrolo- benzoxazin ketone compound and its injection and the purposes in antithrombotic - Google Patents
Pyrrolo- benzoxazin ketone compound and its injection and the purposes in antithrombotic Download PDFInfo
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- CN108912142A CN108912142A CN201810898705.8A CN201810898705A CN108912142A CN 108912142 A CN108912142 A CN 108912142A CN 201810898705 A CN201810898705 A CN 201810898705A CN 108912142 A CN108912142 A CN 108912142A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Abstract
The invention discloses the pyrrolo- benzoxazin ketone compound as shown in compound 1 or its pharmaceutically acceptable salt,.By the extracorporeal platelet aggregation experiment to the compound, the influence to the mouse tail bleeding time and thrombosis experiment is bypassed to Rat Right neck artery-vein, it was found that compound of the present invention can inhibit platelet aggregation, inhibition thrombosis by collagen, adenosine diphosphate and blood coagulation enzymatic pathway.
Description
Technical field
The present invention relates to field of medicaments, and in particular to pyrrolo- benzoxazin ketone compound and its injection and in anti-blood
Purposes in bolt.
Background technique
Cardiovascular and cerebrovascular disease is the general designation of cardiovascular and cranial vascular disease, is referred to since hyperlipidemia, blood are sticky, dynamic
The ischemic or hemorrhagic disease that heart caused by pulse atherosclerosis, hypertension etc., brain and body tissue occur.Heart and brain blood
Pipe disease is that one kind seriously threatens the mankind, and the common disease of especially 50 years old or more middle-aged and the old's health has high illness rate, high cause
The characteristics of residual rate and high mortality, even if the treatment means that application is most advanced, perfect at present, can still there is 50% or more the cerebrovascular
It is unexpected that survivor's life cannot take care of oneself completely, and the number that cardiovascular and cerebrovascular disease is died of in the whole world every year is up to 15,000,000 people, occupy each
The kind cause of the death is the first.
Thrombus is the maximum inducement for leading to cardiovascular and cerebrovascular disease.The blood of Healthy People is collosol state（In liquid condition）,
Under the action of heartbeat, blood can flow in the entire circulatory system not to stop.Once intravascular form thrombus, blood
Circulation nature can be obstructed, by the tissue of embolism or organ will because of ischemic, anoxic and function and organic disease occurs.It is coronal
When artery has thrombosis, in fact it could happen that myocardial infarction；Internal carotid forms thrombus, then apoplexy may occur；Femoral artery has blood
Bolt is formed, and may result in four limbs necrosis；Deep vein thrombosis, which falls off, may result in pulmonary embolism；Extensive thin vessels embolism meeting
Lead to multiple Organ Failures.
Clinically antithrombotic can be divided into anticoagulant, platelet aggregation inhibitor and thrombolytic three categories at present：（1）It is anti-
Coagulant (anticoagulants）There is vitamin K antagon（Warfarin）；Heparin；Direct thrombin inhibitor（Dabigatran
Ester）；Stuart factor inhibitor（Eliquis, razaxaban）.（2）Platelet aggregation-against represent medicine have inhibitors of cyclooxygenases Ah
Take charge of a woods；Adenosine diphosphate (ADP) P2Y12 receptor blocking pharmacon clopidogrel；Phosphodiesterase inhibitors Dipyridamole；Integrin receptor
Blocking agent tirofiban.（3）Thrombus dissolving has urokinase, streptokinase, Alteplase, Reteplase etc., they pass through fibrinolysin
Effect promotes fibrinolysis and thrombus.
With the aggravation of social population's aging, the incidence of thrombotic diseases increasingly increases, and number of patients is more and more.
Since traditional anticoagulant needs to inject or monitor more, by different degrees of limitation in practical application.Therefore, it seeks
The pyrrole looking for new antithrombotic reagent, being of great significance in particular for the drug of platelet aggregation, and mentioned about the present invention
It coughs up and research of the benzoxazin ketone compound in terms of antithrombotic is not yet reported that so far.
Summary of the invention
The present invention provides a kind of pyrrolo- benzoxazin ketone compound, chemical structural formula is：
；
；
。
The compound 1, the structured data of compound 2 and compound 3 and its synthetic method are referring to embodiment part.
The present invention also provides the external influence experiment to platelet aggregation of the compound, to the mouse tail bleeding time
Influence and to Rat Right neck artery-vein bypass thrombosis experiment.
The group of pyrrolo- benzoxazin ketone compound injection prescription of the present invention becomes：The pyrrolo- benzo is disliked
Zionoes compound or 1-20 parts of its pharmaceutically acceptable salt, 40-500 parts of solubilizer, 1-100 parts of isotonic regulator, injection
With 0-200 parts of solvent.The auxiliary material for wherein playing solubilizer is Tween 80, polysorbate40, Emulsifier EL-60, NaTDC
One or more of.Wherein serve isotonic regulator auxiliary material be sodium chloride, glucose, mannitol, lactose, xylitol,
One or more of sorbierite, maltitol, glycerol.Wherein solvent for injection be water, ethyl alcohol, glycerol, Liquid Macrogol,
One or more of polyethylene glycol 400.It also may be selected that other solubilizer with solubilization, other make with isotonic adjusting
Isotonic regulator and other solvent for injection are applied in the present invention.
Preparation method of the invention includes the following contents：
By the solubilizer of recipe quantity, pyrrolo- benzoxazin ketone compound or its pharmaceutically acceptable salt and other solubilities
Auxiliary material is dissolved in solvent for injection respectively in sequence, and through decoloration, filtering, sterilize to obtain injection.
Detailed description of the invention
Fig. 1 is influence of the compounds of this invention to the mouse tail bleeding time.
Specific embodiment
Embodiment 1：The synthesis of compound 1
Dimethyl 2- is added in reaction flask（2-（4- methoxyphenyl）- 2- oxygen ethylethylene residue）Dimethyl malenate（0.25
mmoL）,（Z）Methyl 2-（2- oxo -2H- benzo [b] [1,4] oxazines -3（4H）Methylene）Acetic acid esters（0.3 mmoL）With
Dichloroethanes（2 mL）, it is stirring evenly and then adding into ferric trichloride（0.25 mmoL）.80 DEG C of reaction solution stirrings, TLC monitoring have been reacted
It is concentrated under reduced pressure after complete, residue column chromatographic purifying obtains compound 1.Through structural identification, synthesized compound1H-NMR and13C-NMR data and document（FeCl3-Mediated Domino Reaction of Benzoxazinones with
Aroylmethylidene Malonates: Synthesis to Functionalized Pyrrolobenzoxazines
（J. Org. Chem. 2017, 82, 13617−13625））Unanimously.
Embodiment 2：The synthesis of compound 2
2- methyl -2- is added in reaction flask（2- oxo -2-（Thiophene -2- base）Ethylidene）Dimethyl malenate（0.25 mmoL）,
（Z）Methyl 2-（2- oxo -2H- benzo [b] [1,4] oxazines -3（4H）Methylene）Acetic acid esters（0.3 mmoL）With two chloroethenes
Alkane（2 mL）, it is stirring evenly and then adding into ferric trichloride（0.25 mmoL）.80 DEG C of reaction solution stirrings subtract after TLC monitoring fully reacting
Pressure concentration, residue column chromatographic purifying obtain compound 2.Through structural identification, synthesized compound1H-NMR and13C-NMR number
According to document（FeCl3-Mediated Domino Reaction of Benzoxazinones with
Aroylmethylidene Malonates: Synthesis to Functionalized Pyrrolobenzoxazines
（J. Org. Chem. 2017, 82, 13617−13625））Unanimously.
Embodiment 3：The synthesis of compound 3
2- is added in reaction flask（2- oxo -2- phenyl-ethylene）Dimethyl malenate（0.25 mmoL）,（（Z）-3-（2- methoxy
Base -2- oxo ethylidene）- 2- oxo -3,4- dihydro -2H- benzo [b] [1,4] oxazines -6- carboxylate methyl ester（0.3 mmoL）With
Dichloroethanes（2 mL）, it is stirring evenly and then adding into ferric trichloride（0.25 mmoL）.80 DEG C of reaction solution stirrings, TLC monitoring have been reacted
It is concentrated under reduced pressure after complete, residue column chromatographic purifying obtains compound 3.Through structural identification, synthesized compound1H-NMR and13C-NMR data and document（FeCl3-Mediated Domino Reaction of Benzoxazinones with
Aroylmethylidene Malonates: Synthesis to Functionalized Pyrrolobenzoxazines
（J. Org. Chem. 2017, 82, 13617−13625））Unanimously.
Embodiment 4：Prepare 200 1 injections of compound（5 mL of specification：50 mg）
One, prescription
1 10 g of compound, 200 g of Tween 80,1.25 g of sodium chloride, water for injection add to 1000 mL.
Two, preparation process
The Tween 80 of recipe quantity is dissolved in the fresh water for injection of recipe quantity 80%, compound 1 is added, 10-20 is stirred at room temperature
Min dissolves it all.The sodium chloride of recipe quantity is added, water for injection is added after stirring and dissolving to 1000 mL.It is added 0.1%
60 DEG C of active carbon 15 min of heat preservation, through 0.22 μm of filtering with microporous membrane after letting cool.Filtrate encapsulating is 5 mL injections, and 121 DEG C go out
15 min of bacterium to obtain the final product.
Embodiment 5：Prepare 200 2 injections of compound（5 mL of specification：50 mg）
One, prescription
2 10 g of compound, 200 g of Tween 80,1.25 g of sodium chloride, water for injection add to 1000 mL.
Two, processing step
The Tween 80 of recipe quantity is dissolved in the fresh water for injection of recipe quantity 80%, compound 2 is added, 10-20 is stirred at room temperature
Min dissolves it all.The sodium chloride of recipe quantity is added, water for injection is added after stirring and dissolving to 1000 mL.It is added 0.1%
60 DEG C of active carbon 15 min of heat preservation, through 0.22 μm of filtering with microporous membrane after letting cool.Filtrate encapsulating is 5 mL injections, and 121 DEG C go out
15 min of bacterium to obtain the final product.
Embodiment 6：Prepare 200 1 injections of compound（10 mL of specification：80 mg）
One, prescription
1 16 g of compound, 400 g of Tween 80,13.9 g of glucose, water for injection add to 2000 mL.
Two, processing step
The Tween 80 of recipe quantity is dissolved in the fresh water for injection of recipe quantity 80%, compound 1 is added, 10-20 is stirred at room temperature
Min dissolves it all.The glucose of recipe quantity is added, water for injection is added after stirring and dissolving to 2000 mL.It is added 0.1%
60 DEG C of active carbon 15 min of heat preservation, through 0.22 μm of filtering with microporous membrane after letting cool.Filtrate encapsulating be 10 mL injections, 121 DEG C
Sterilize 15 min to obtain the final product.
Embodiment 7：Prepare 200 2 injections of compound（10 mL of specification：80 mg）
One, prescription
2 16 g of compound, 400 g of Tween 80,13.9 g of glucose, water for injection add to 2000 mL.
Two, processing step
The Tween 80 of recipe quantity is dissolved in the fresh water for injection of recipe quantity 80%, compound 2 is added, 10-20 is stirred at room temperature
Min dissolves it all.The glucose of recipe quantity is added, water for injection is added after stirring and dissolving to 2000 mL.It is added 0.1%
60 DEG C of active carbon 15 min of heat preservation, through 0.22 μm of filtering with microporous membrane after letting cool.Filtrate encapsulating be 10 mL injections, 121 DEG C
Sterilize 15 min to obtain the final product.
Embodiment 8：Prepare 200 1 injections of compound（5 mL of specification：100 mg）
One, prescription
1 20 g of compound, 400 g of Tween 80, water for injection add to 1000 mL.
Two, processing step
The Tween 80 of recipe quantity is dissolved in the fresh water for injection of recipe quantity 80%, compound 1 is added, 10-20 is stirred at room temperature
Water for injection is added after stirring and dissolving to 1000 mL by min.0.1% active carbon, 60 DEG C of 15 min of heat preservation are added, through 0.22 after letting cool
μm filtering with microporous membrane.Filtrate encapsulating is 5 mL injections, and 121 DEG C of 15 min of sterilizing to obtain the final product.
Embodiment 9：Prepare 200 2 injections of compound（5 mL of specification：100 mg）
One, prescription
2 20 g of compound, 400 g of Tween 80, water for injection add to 1000 mL.
Two, processing step
The Tween 80 of recipe quantity is dissolved in the fresh water for injection of recipe quantity 80%, compound 2 is added, 10-20 is stirred at room temperature
Water for injection is added after stirring and dissolving to 1000 mL by min.0.1% active carbon, 60 DEG C of 15 min of heat preservation are added, through 0.22 after letting cool
μm filtering with microporous membrane.Filtrate encapsulating is 5 mL injections, and 121 DEG C of 15 min of sterilizing to obtain the final product.
Embodiment 10：Prepare 200 sun ginseng clopidogrel injections（5 mL of specification：100 mg）
One, prescription
20 g of clopidogrel, 400 g of Tween 80, water for injection add to 1000 mL.
Two, preparation process
The Tween 80 of recipe quantity is dissolved in the fresh water for injection of recipe quantity 80%, clopidogrel is added, 10-20 is stirred at room temperature
Water for injection is added after stirring and dissolving to 1000 mL by min.0.1% active carbon, 60 DEG C of 15 min of heat preservation are added, through 0.22 after letting cool
μm filtering with microporous membrane.Filtrate encapsulating is 5 mL injections, and 121 DEG C of 15 min of sterilizing to obtain the final product.
Test example 1：Influence of the compound 1-3 to extracorporeal platelet aggregation
Blood platelet can be assembled by approach such as collagen, adenosine diphosphate, fibrin ferments, lead to blood clotting.Therefore, different ways are studied
The platelet aggregation of diameter has great importance to the mechanism of research drug platelet aggregation-against.
Rat carotid artery takes blood, conventionally prepares platelet rich plasma（PRP）And platelet poor plasma（PPP）,
It and with platelet count in PPP tune PRP is 4.0-6.0 × 108A/mL takes 200 μ L of PRP, being separately added into referring to BornShi method
Close object 1, compound 2, compound 3 and aspirin（Final concentration is 100 μm of ol/L）, it is placed on intelligent blood platelet gathering instrument,
After 37 DEG C of 5 min of pre-temperature, it is separately added into four kinds of induced polymerization inhibitors：Collagen（Final concentration of 50 μ l/mL）, adenosine diphosphate（It is final concentration of
5 μmol/L）, fibrin ferment（Final concentration of 1 U/mL）, arachidonic acid（Final concentration of 0.5 mmol/L）, measure in induced polymerization inhibitor
Platelet aggregation rate after 5 min are added.As a result it see the table below 1.
The rat platelet aggregation rate that 1 compound 1-3 of table induces different induced polymerization inhibitors
| It is collagen-induced（%） | Adenosine diphosphate induction（%） | Thrombin induction（%） | Arachidonic acid-induction（%） | |
| Compound 1 | 39.5±3.3 | 23.4±2.1 | 50.0±5.7 | 70.3±7.2 |
| Compound 2 | 42.8±3.7 | 29.2±3.4 | 52.7±6.0 | 77.6±8.0 |
| Compound 3 | 78.1±4.4 | 65.7±3.8 | 75.9±6.7 | 74.5±7.0 |
| Aspirin | 40.9±8.0 | 71.2±7.7 | 52.9±6.6 | 0±0 |
Test result shows that compound 1 and compound 2 have the platelet aggregation of collagen, adenosine diphosphate, thrombin induction
Certain inhibiting effect, but it is poor to the Platelet aggregation inhibitor ability of arachidonic acid-induction；Compound 1 is to collagen, adenosine two
Phosphoric acid, thrombin induction Platelet aggregation inhibitor ability be better than compound 2.Rat serum of the compound 3 to four kinds of poly- agent inductions
It is weak that platelet assembles rejection ability.
Test example 2：Influence of the compound 1-3 to the mouse tail bleeding time
1, grouping and dosage：
70 male mices are randomly divided into 7 groups, respectively blank control group（Same amount of normal saline）, 1 group of compound（80 mg/
kg,120 mg/kg）, 2 groups of compound（80 mg/kg,120 mg/kg）, sun ginseng clopidogrel group（80 mg/kg,120 mg/
kg）.
2, experimental method：
Gastric infusion, 1 time a day, for three days on end, in 1.5 h after the last administration, mouse is fixed, and tail is vertical, away from 1.5 mm of tail point
After tail portion is cut at place, tail portion is placed in 37 DEG C of physiological saline, every group of every mouse bleeding time is recorded：I.e. cut tail point start to
Until blood stops outflow.Bleeding time is more than that 10 min persons are calculated with 10 min.
Test result is as shown in Figure 1.Compound 1 and compound 2 can extend the bleeding time of experimental mouse docking.80
Under mg/kg dosage, the bleeding time of compound 1>Clopidogrel>Compound 2；Under 120 mg/kg dosage, compound 1 goes out
Blood time longest.For 80 mg/kg of compound 1 compared with 120 mg/kg dosage, the high dose bleeding time is longer.
Test example 3：Embodiment 8, embodiment 9 and 10 injection of embodiment bypass thrombosis to Rat Right neck artery-vein
Experiment
1, experimental drug：
Physiological saline, 8 injection of embodiment, 9 injection of embodiment, 10 sun ginseng clopidogrel injection of embodiment.
2, grouping and dosage：
Wistar rat 40, half male and half female is randomly divided into 4 groups, every group 10.Blank control group（Same amount of normal saline）, real
Apply 8 injection group of example（120 mg/kg）, 9 injection group of embodiment（120 mg/kg）, 10 sun ginseng clopidogrel injection of embodiment
Liquid（120 mg/kg）.
3, experimental method：
Groups of animals presses above-mentioned dosage intraperitoneal administration, and blank control group gives same amount of normal saline, one time a day, continuous 5 d, in
30 min are fixed after the last administration with chloraldurate (350 mg/kg) anesthesia, dorsal position, separate tracheae, are inserted into a plastic bushing,
And isolate right carotid and left vena jugularis externa.6 cm of a root long is put into polyethylene pipe middle section to have weighed silk thread.With heparin (50
U/mL) it is full of polyethylene pipe.Left neck vein is inserted into one end of pipe, and other end injection heparin (50 U/kg) is anticoagulant, and it is dynamic to be inserted into right neck
Arteries and veins.Artery clamp is opened, blood flows through polyethylene pipe by right carotid and returns to left neck vein.Open 15 min of blood flow, middle clinopodium polycephalum,
Silk thread weighing is taken out rapidly, and gross weight subtracts line weight up to wet weight of thrombus.Measurement result is shown in Table 3.
Influence of the table 3 to rat artery-vein bypass thrombosis
| Grouping | Wet weight of thrombus（mg） |
| Blank control group | 55.19±4.02 |
| 8 groups of embodiment | 29.86±3.05 |
| 9 groups of embodiment | 44.27±3.22 |
| Embodiment 10（Sun ginseng clopidogrel）Group | 38.01±3.37 |
Experimental result is shown, compared with blank control group, embodiment 8, embodiment 9 can reduce wet weight of thrombus.Join chlorine pyrrole with sun
Gray compares, and the ability of 8 inhibition thrombosis of embodiment is stronger.
Claims (8)
1. pyrrolo- benzoxazin ketone compound or its pharmaceutically acceptable salt, chemical structural formula are：
；
；
。
2. pyrrolo- benzoxazin ketone compound as described in claim 1 or its pharmaceutically acceptable salt are as antithrombotic
Application.
3. pyrrolo- benzoxazin ketone compound as described in claim 1 or its pharmaceutically acceptable salt are as antithrombotic
Application, in particular for platelet aggregation.
4. injection as described in claim 1, containing pyrrolo- benzoxazin ketone compound or its is pharmaceutically acceptable
Salt active constituent, solubilizer, isotonic regulator, solvent for injection.
5. injection as claimed in claim 4, it is characterized in that the pyrrolo- benzoxazin ketone compound or its pharmaceutically
The prescription proportion of acceptable salt is 1-20 parts.
6. injection as claimed in claim 4, it is characterized in that the solubilizer is selected from Tween 80, polysorbate40, polyoxyethylene castor
One or more of sesame oil, NaTDC, the solubilizer prescription proportion is 40-500 parts.
7. injection as claimed in claim 4, it is characterized in that the isotonic regulator be selected from sodium chloride, glucose, mannitol,
One or more of lactose, xylitol, sorbierite, maltitol, glycerol, the isotonic regulator prescription proportion is 1-100
Part.
8. injection as claimed in claim 4, it is characterized in that the solvent for injection is selected from water, ethyl alcohol, glycerol, polyethylene glycol
300, one or more of polyethylene glycol 400, the solvent for injection prescription proportion is 0-200 parts.
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|---|---|---|---|---|
| WO2007075809A3 (en) * | 2005-12-22 | 2008-02-21 | Schering Corp | Oxazoloisoquinoline derivatives as thrombin receptor antagonists |
| CN101318968A (en) * | 2008-07-18 | 2008-12-10 | 青岛黄海制药有限责任公司 | Benzoxazine-pyrazoles and opened loop compound |
| WO2015043364A1 (en) * | 2013-09-29 | 2015-04-02 | 华北制药集团新药研究开发有限责任公司 | Benzoxazoleoxazine ketone compound as blood coagulation factor xa inhibitor |
| CN105218564A (en) * | 2014-07-02 | 2016-01-06 | 中国科学院上海药物研究所 | San Huan oxazolidinone compounds and its production and use |
| EP2947085A4 (en) * | 2013-01-18 | 2016-06-22 | Shanghai Inst Materia Medica | Oxazolidone compound, preparing method and application thereof |
-
2018
- 2018-08-08 CN CN201810898705.8A patent/CN108912142B/en not_active Expired - Fee Related
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| WO2007075809A3 (en) * | 2005-12-22 | 2008-02-21 | Schering Corp | Oxazoloisoquinoline derivatives as thrombin receptor antagonists |
| CN101318968A (en) * | 2008-07-18 | 2008-12-10 | 青岛黄海制药有限责任公司 | Benzoxazine-pyrazoles and opened loop compound |
| EP2947085A4 (en) * | 2013-01-18 | 2016-06-22 | Shanghai Inst Materia Medica | Oxazolidone compound, preparing method and application thereof |
| WO2015043364A1 (en) * | 2013-09-29 | 2015-04-02 | 华北制药集团新药研究开发有限责任公司 | Benzoxazoleoxazine ketone compound as blood coagulation factor xa inhibitor |
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