CN107827882B - A kind of razaxaban analog and its purposes for treating thrombus - Google Patents
A kind of razaxaban analog and its purposes for treating thrombus Download PDFInfo
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- CN107827882B CN107827882B CN201711201460.0A CN201711201460A CN107827882B CN 107827882 B CN107827882 B CN 107827882B CN 201711201460 A CN201711201460 A CN 201711201460A CN 107827882 B CN107827882 B CN 107827882B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
The invention belongs to field of medicinal chemistry, and in particular to a kind of razaxaban analog and its purposes for treating thrombus.Razaxaban analog of the present invention is that aspirin and chloride reagent act on after generating 2- acetoxyl group chlorobenzoyl chloride and be condensed generation under certain condition with 4- [4- [(5S) -5- (aminomethyl) -2- carbonyl -3- oxazolidinyl] phenyl] -3- morpholine ketone again.The invention also discloses the pharmaceutical salts of razaxaban analog, the pharmaceutical composition comprising compound or its salt, and the purposes of the inhibitor as the FXa factor, further prepare the medical usage in anticoagulant.More particularly to it as the purposes in preparation prevention or treatment thrombosis or thrombosis drug.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a kind of razaxaban analog, the pharmaceutical salts of compound include
The pharmaceutical composition of compound or its salt, the purposes of the inhibitor as the FXa factor further prepare the doctor in anticoagulant
Medicinal way.More particularly to it as the purposes in preparation prevention or treatment thrombosis or thrombosis drug.
Background technique
Thrombotic diseases are the diseases for seriously endangering human health, according to thrombosis position, condition and property, main point
For arterial thrombus and phlebothrombosis.Arterial thrombosis is opened from arterial blood tube wall atherosclerotic lesion with platelet activation
Begin, caused bad clinical reaction is mainly acute myocardial infarction AMI, cerebral apoplexy；Phlebothrombosis is by many reasons in vein blood vessel
It induces and is formed, be can lead to venous thromboembolism (venous thromboembolism, VTE), main clinical manifestation is deep quiet
Arteries and veins thrombosis (deep venous thrombosis, DVT) and pulmonary embolism (pulmonary embolism, PE).VTE is
The third-largest cardiovascular disease after acute coronary syndrome and cerebral apoplexy.In all deaths of hospital, VTE accounts for about
Sum 1,000,000 occurs for 10%, the annual VTE of 6 state, European Union, and death number is more than AIDS, breast cancer, prostate cancer and traffic thing
Therefore murderous summation.U.S.'s death is then more than 29.6 ten thousand/year, and lethal PE is made a definite diagnosis before death less than 50%.
Prevention VTE is classified as by associated guideline in the world reduces one of most important strategy of the inpatient death rate.
Clinical trial evidence shows that anticoagulant therapy can prevent the sprawling and recurrence of thrombus, and further decreases soldier
In, the incidence and the death rate of PE etc..Therefore, anticoagulant therapy has become current clinical prevention and treatment thrombotic disease
Core and basis, and the research and development of anticoagulant are also the hot spot of new drug development always, traditional anticoagulation, such as heparin leech
There are many side effects, such as haemolysis and hemorrhagic tendency, using effects simultaneously to pay no attention to for element, argatroban, warfarin, clopidogrel etc.
Think.
The FXa factor (factor X activated, factor FXa) is a kind of serine protease, is located at blood coagulation
Cascade upstream is in the center of connection endogenous and exogenous activated pathway co-channel, and FXa factor inhibitors can
Block intrinsic coagulation that can also inhibit the generation of extrinsic coagulation.The FXa factor is the speed limit ingredient that fibrin ferment generates, due in blood
There is also the amplification of bio signal in liquid coagulation cascade reaction process, estimate that a FXa factor inhibitors molecule can inhibit 138
The physiologic effect of a prothrombin molecule, FXa factor inhibitors may be more more effective than thrombin inhibitor.The FXa factor is only simple
Promote blood coagulation, do not prevent platelet aggregation, not the side effect of thrombin inhibitor, therefore, FXa factor inhibitors become close
One of the hot spot that anticoagulation medicine is studied over year.
Since the razaxaban (visiing auspicious appropriate) of Bayer Bitterfeld GmbH pharmacy, there is Eliquis successively, on the drugs such as Yi Dushaban
City, shellfish Qu Shaban, Tak-442 etc. enter clinical trial, and Tianjin Inst. of Materia Medica independent research knows that Fei Shaban piece has also existed
The clinic official written reply of acquisition in 2015.Traditional anticoagulation such as warfarin etc. is gradually substituted, it remains desirable, however, that develop more FXa because
Sub- inhibitor.
Aspirin is a kind of century drug, with a variety of pharmacological activity, wherein has anti-blood small when low dosage uses
The effect of plate aggregation in the prior art carries out the combination of razaxaban and other drugs so as to the generation of pre- preventing thrombosis
A variety of trials, however with the combination of aspirin and failed, the two combination can not significantly improve anticoagulating active, increase instead
Add the risk of bleeding.
The most common adverse reaction of aspirin is exactly gastrointestinal reaction, such as nausea, epigastric discomfort, vomiting.It is oral
Aspirin can directly stimulate gastric mucosa so as to cause epigastric discomfort and nausea and vomiting, and aspirin is such as used for a long time, and hold
Easily lead to the damage of stomach lining.
Summary of the invention
The present invention relates to inhibitor of the razaxaban analog as the FXa factor shown in chemical formula (I), and its are preparing
Purposes in anticoagulant, more specifically, the purposes in preparation prevention or treatment thrombus or thrombosis drug.
It is an advantage of the invention to provide the compound of structure shown in following chemical formula (I), its is pharmaceutical
Salt:
Another object of the present invention is to provide the preparation method for preparing above-mentioned formula (I) compound, the method includes
Following steps:
1) aspirin and chloride reagent effect generate 2- acetoxyl group chlorobenzoyl chloride, the chloride reagent include but
It is not limited to thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride.
2) 4- [4- [(5S) -5- (aminomethyl) -2- carbonyl -3- oxazolidinyl] phenyl] -3- morpholine ketone, 2- acetyloxy phenyl
Formyl chloride is condensed the corresponding product of generation under the conditions of such as DIPEA, DMAP, DCM.
It is a further object of the present invention to provide compounds shown in above-mentioned chemical formula (I) in preparation FXa factor inhibitors
The purposes of drug more particularly provides above-mentioned chemical formula (I) specifically as the purposes prepared in anticoagulation medicine
Shown compound is as the purposes in the purposes drug of preparation prevention and/or treatment thrombosis or embolism.By to people FXa's
Inhibiting effect test, the compounds of this invention show excellent FXa inhibitory activity；Pass through the shadow to normal mouse APTT
Loud pharmacodynamic test, the compounds of this invention equal extremely significant APTT value for increasing mouse of energy after 60min is administered, shows good
Anticoagulation；By the development test to normal rat pharmacokinetics, it is dynamic that the compounds of this invention shows excellent medicine
Feature is learned, aspirin is slowly released in the metabolic process, to enhance anticoagulant effect, and due to aspirin and change
Formula (I) compound concentration peak and non-concurrent appearance in blood, to overcome razaxaban and aspirin combination use
The shortcomings that Shi Zengjia bleeding risk, also without the side effect of aspirin often some stimulations stomach mucosa.
Specific embodiment
The present invention is described in further detail with test example with reference to embodiments, but not to limit of the invention
System, all equivalent replacements according to any this field made by the disclosure of invention all belong to the scope of protection of the present invention.
The structure of compound by mass spectrum (MS) or nuclear magnetic resonance (1HNMR it) determines.
Nuclear magnetic resonance (1HNMR) displacement (δ) is provided with the unit of hundred a ten thousandths (ppm)；Nuclear magnetic resonance (1HNMR survey)
It surely is to use BrukerAVANCE-400 nuclear magnetic resonance spectrometer, measurement solvent is deuterated DMSO, is inside designated as tetramethylsilane (TMS).
The measurement of mass spectrum (MS) is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Therm, model: Finnigan
LCQ advantage MAX) it carries out.
Column chromatography fills column using 200-300 mesh silica gel.
The present invention do not provide specified otherwise in the case where, the present invention mentioned in reaction under anhydrous and oxygen-free into
Row.
Refer to that temperature is between 20 DEG C -25 DEG C in term " room temperature " of the invention.
Raw material used in the present invention is commercial product, wherein (S) -2- ((2- oxo -3- (4- (3- oxomorpholin generation)
Phenyl) oxazolidine -5- ylmethyl) iso-indoles -1,3- diketone be synthesize razaxaban important intermediate, a variety of sides can be passed through
Method synthesis, repeats no more its preparation in this application.
Embodiment
The preparation of embodiment 1:2- acetoxyl group-chlorobenzoyl chloride
Under the conditions of anhydrous and oxygen-free, 2- acetoxy-benzoic is added into methylene chloride, is added thionyl chloride (1.5eq),
The n,N-Dimethylformamide (1%) of catalytic amount reacts at room temperature 3h.A small amount of reaction solution is taken, methanol is added, TLC monitoring is reacted, to
After fully reacting, reduced pressure at room temperature removes solvent, is washed with methylene chloride, and revolving removes solvent and (washes 2 times, so that dichloro is sub- at room temperature
Sulfone removal is clean), it is purified without further, is directly used in and reacts in next step.
Embodiment 2: there is the preparation of the compound of chemical formula (I)
Under the conditions of anhydrous and oxygen-free, by (S) -2- ((2- oxo -3- (4- (3- oxomorpholin generation) phenyl) oxazolidine -5- Ji Jia
Base) iso-indoles -1,3- diketone (V, 1mmol) is dissolved in methylene chloride, it is added n,N-diisopropylethylamine (2.0eq), 2- second
Acyloxy-chlorobenzoyl chloride (IV, 1.5eq), room temperature reaction is overnight.TLC monitoring reaction is washed twice, dichloromethane to fully reacting
Alkane extraction, column chromatographic isolation and purification obtain the compound with chemical formula (I), with (V) calculating, yield 73%.
MS (ESI): m/z (%)=454.5 ([M+H]+)
1H NMR:2.41 (3H, s), 3.35-3.60 (6H, m), 3.77-3.91 (2H, d), 4.30 (2H, s), 5.93 (1H,
M), 6.85 (2H, d), 7.16 (2H, d), 7.36 (1H, t) 7.90 (2H, m), 8.11 (1H, d), 8.45 (1H, t)
Test example I: the influence to normal mouse APTT
1, test objective
Blood coagulation four (including prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time
(TT), fibrinogen (FIB)), belong to one of visiting inspection item, is that thrombotic diseases inspection or operation consent must look into project.
APTT mainly reflects whether intrinsic coagulation system situation is normal.Therefore, the present invention refers to APTT value as the detection of this test
Mark evaluates its anticoagulation by studying influence of the compound of the embodiment of the present invention to mouse APTT.
2, experimental material
2.1 test drugs:
Positive drug: razaxaban bulk pharmaceutical chemicals, commercially available product, purity: 99.3%；
Test drug: 2 compound of embodiment, white solid, purity: 98.7%；
2.2 test equipments:
Sysmex CA7000 type full-automatic blood coagulation analyzer is produced by Japanese Sysmex company；
Roche C501 automatic clinical chemistry analyzer, is produced by Roche；
Ophthalmic tweezers, gastric perfusion needle, mortar, vacuum blood collection tube, syringe etc..
2.3 experimental animals:
KM mouse, 28~30g of weight, male, 60.Raising is in animal house, adaptability observation at least 3 after animal is bought back
It, for testing after quarantine is qualified.
3, test method
(1) it is grouped: being tested according to the grouping of table 1, wherein every group of mouse is 20.
The test of table 1 grouping and dosage regimen
(2) APTT is measured: each group gives corresponding test drug (blank group gives physiological saline), and after 1h is administered, eye socket takes blood
In the 0.5ml vacuum blood collection tube containing sodium citrate, the APTT value of measurement animal after blood sample is acquired.
4, statistical method:
It is counted using Excel, compares between multiple groups and statistics comparison is carried out using the bilateral T method of inspection.
5, test result
Table 2 implements influence of the compound to mouse APTT
| Group | Number of animals (only) | Dosage (mg/kg) | APTT(sec) |
| Blank group | 20 | - | 17.66±1.10 |
| Positive group | 20 | 5 | 23.45±1.01 |
| To be measured group | 20 | 5 | 22.91±0.77 |
6, conclusion
Table 2 is the results show that compared to the blank group, and after 1h is administered, the APTT value of positive group and each embodiment group is dramatically increased,
Illustrate that razaxaban and 2 compound of the embodiment of the present invention can dramatically increase the APTT value of mouse after 1h is administered；
Test example II: inhibiting effect of the compounds of this invention to people FXa
1, test objective
Compound of the embodiment of the present invention is studied to the inhibiting effect of people FXa, measures the IC50 inhibited to people FXa.
2, test material
2.1, drug:
Positive drug: razaxaban bulk pharmaceutical chemicals, purity: 99.0%；
Test drug: 2 compound of embodiment, purity: 98.2%.
2.2, test equipment:
EnVision multiple labeling detector (Perkin Elmer company)；
Human FXa enzyme (Sekisui Diagnostics, REF526)；
Fluorogenic substrate for the FXa assay (American diagnostic, Product
No.222F)；
384-well assay plate (Corning, Cat.3573)；
Buffer: 20mM Tris-HCl, 200mM NaCl, 2.5mM CaCl2, pH8.0.
2.3, test method:
(1) before the use, 2 compound of embodiment and razaxaban are dissolved into 10mM with DMSO；
(2) each compound of 10mM is taken, the compound gradient of 10 times of concentration is diluted to buffer, 40 μM are arrived
0.002048nM (5 times of dilutions)；
The compound solution of 6 μ L10 times concentration is added in every hole in (3) 384 orifice plates.Final volume is 60 μ L, final compound concentration
Range is from 4 μM to 0.0002048nM；
(4) 30 μ L people FXa enzymes (2nM), final concentration of 1nM is added in every hole；
(5) 24 μ L people's FXa enzyme fluorescence chromophoric substrates (266.7 μM) of every hole addition, final concentration of 106.7 μM；
(6) it gently shakes 5 minutes, is then incubated at room temperature 30 minutes, is protected from light；
(7) 360/440nm fluorescence is read, and measures percent inhibition, using the 4Parameter in Xlfit software
Logistic Model calculates IC50。
3, test result:
Table 3: inhibiting effect of the embodiment compound to people FXa
| Group | Compound | IC50(nM) |
| To be measured group | 2 compound of embodiment | 1.02 |
| Positive control | Razaxaban | 0.72 |
From 3 compound of table to the inhibition test data of people FXa it is found that the compound of the present invention inhibits with significant FXa
It is slightly poor that activity and positive drug razaxaban compare, but is still enough to prepare anticoagulant as FXa inhibitor.
Test example III: the influence to rat suppository dry weight
Rat 60 are grouped by weight average, 24 hours anesthetized animals after single oral gavage administration (urethane, 1.25g/kg,
ID) dorsal position is fixed, and separates right common carotid artery and left external carotid artery.The silk of the own weighing of 5cm is put into polyfluortetraethylene pipe
Line is full of polytetrafluoroethylene (PTFE) pipeline with heparin-saline solution (50u/m1).When left neck is inserted into one end of polyfluortetraethylene pipe
After outer vein, anticoagulant heparin is accurately injected by polyfluortetraethylene pipe, the other end of polyfluortetraethylene pipe is then inserted into right neck again
Total artery.Artery clamp is opened, middle clinopodium polycephalum after open blood flow 30min takes out rapidly silk thread weighing, it can obtain wet weight of thrombus, 60 DEG C
It is one hour dry, it weighs after restoring room temperature, thrombus dry weight can be obtained.
The influence that 4 oral administration of compound of table forms arteriovenous shunt thrombosis
Above-mentioned test result shows that 2 compound of the embodiment of the present invention shows significant FXa inhibitory activity, blood coagulation activity
And excellent pharmacokinetic property, it can be used for preparing FXa factor inhibitors drug, further can be used for preparing anticoagulation
Object is further used to prepare prevention or treatment thrombus or thrombosis drug.
Although the compounds of this invention is slightly below razaxaban for the inhibitory activity of the FXa factor, in terms of antithrombotic
Show more preferably effect, thus it is speculated that the reason is that amido bond hydrolysis releases aspirin institute when compound is metabolized in vivo
It causes.Razaxaban and aspirin have bleeding risk when being combined, however the aspirin of the application is discharged by compound hydrolysis
Out, therefore its peak concentration is staggered with having the compound of chemical formula (I), has effectively evaded this risk, while also dropping
The effect fluctuation of low antithrombotic.
Show that compound of the embodiment of the present invention shows excellent anticoagulation and pharmacokinetics row according to the above results
For, can be to this hair for the ordinary skill in the art it is apparent that without departing from spirit or scope of the invention
A variety of modification and transformations that bright compound, composition and method carry out, therefore, the present invention include to modification and change of the invention
Change, as long as in claim and its equivalent range.
Claims (6)
1. chemical formula (I) compound represented and pharmaceutically acceptable salt
2. the synthetic method of chemistry formula (I) compound, is reached by following reaction route described in claim 1,
3. the pharmaceutical composition comprising chemistry formula (I) compound described in claim 1, it includes the chemical formulas of therapeutically effective amount
(I) compound and pharmaceutically acceptable auxiliary material.
4. the purposes of compound described in claim 1 in medicine preparation, which is characterized in that the drug is that FXa inhibits
Agent.
5. the purposes of pharmaceutical composition as claimed in claim 3 in medicine preparation, which is characterized in that the drug is FXa
Inhibitor.
6. purposes described in claim 4 or 5, which is characterized in that the drug is for preventing and/or treating thromboembolia type
Disease or illness.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711201460.0A CN107827882B (en) | 2017-11-27 | 2017-11-27 | A kind of razaxaban analog and its purposes for treating thrombus |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711201460.0A CN107827882B (en) | 2017-11-27 | 2017-11-27 | A kind of razaxaban analog and its purposes for treating thrombus |
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| CN107827882A CN107827882A (en) | 2018-03-23 |
| CN107827882B true CN107827882B (en) | 2019-12-03 |
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| CN111333635A (en) * | 2020-04-16 | 2020-06-26 | 东南大学 | Rivaroxaban impurity reference substance and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105348275A (en) * | 2015-12-10 | 2016-02-24 | 中国药科大学 | Oxazolidinone compound and synthetic method and medical application of oxazolidinone compound |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10105989A1 (en) * | 2001-02-09 | 2002-08-14 | Bayer Ag | Substituted oxazolidinones and their use |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105348275A (en) * | 2015-12-10 | 2016-02-24 | 中国药科大学 | Oxazolidinone compound and synthetic method and medical application of oxazolidinone compound |
Non-Patent Citations (4)
| Title |
|---|
| Combined chemical feature-based assessment and Bayesian model studies to identify potential inhibitors for Factor Xa.;Meganathan Chandrasekaran, et al.,;《Med Chem Res》;20111230;第21卷;第4083–4099页. * |
| Discovery of the Novel Antithrombotic Agent 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (BAY 59-7939): An Oral, Direct Factor Xa Inhibitor.;Susanne Roehrig, et al.,;《J.Med.Chem.》;20050818;第48卷;第5900-5908页. * |
| 利伐沙班衍生物的合成及Xa因子抑制活性.;高娜娜等，;《中国药科大学》;20111231;第42卷(第5期);第392-399页. * |
| 噁唑烷酮醚类化合物的合成及其Xa因子抑制活性.;李慧等，;《中国药科大学学报》;20131231;第44卷(第5期);第385-389页. * |
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