CN107827882A - 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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- CN107827882A CN107827882A CN201711201460.0A CN201711201460A CN107827882A CN 107827882 A CN107827882 A CN 107827882A CN 201711201460 A CN201711201460 A CN 201711201460A CN 107827882 A CN107827882 A CN 107827882A
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- C07—ORGANIC CHEMISTRY
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- 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
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Abstract
The invention belongs to medicinal chemistry art, and in particular to a kind of razaxaban analog and its purposes for treating thrombus.Razaxaban analog of the present invention is aspirin with being condensed generation under certain condition with 4 [4 [oxazolidinyl of (5S) 5 (aminomethyl) 2 carbonyl 3] phenyl] 3 morpholine ketone again after chloride reagent effect 2 acetoxyl group chlorobenzoyl chlorides of generation.The invention also discloses the pharmaceutical salts of razaxaban analog, the pharmaceutical composition of inclusion compound or its salt, and the purposes of the inhibitor as the FXa factors, further prepare the medical usage in anticoagulant.More particularly to it as the purposes prepared in prevention or treatment thrombosis or thrombosis drug.
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to a kind of razaxaban analog, the pharmaceutical salts of compound, comprising
The pharmaceutical composition of compound or its salt, as the purposes of the inhibitor of the FXa factors, further prepare the doctor in anticoagulant
Medicinal way.More particularly to it as the purposes prepared in prevention or treatment thrombosis or thrombosis drug.
Background technology
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, its caused bad clinical reaction is mainly acute myocardial infarction AMI, cerebral apoplexy；Phlebothrombosis is by many reasons in vein blood vessel
Induce and formed, VTE (venous thromboembolism, VTE) can be caused, its 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 angiocardiopathy after acute coronary syndrome and cerebral apoplexy.In all deaths of hospital, VTE is accounted for
10%, sum 1,000,000 occurs for the annual VTE of state of European Union 6, and death number exceedes 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 makes a definite diagnosis less than 50% before death.
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 reduce soldier
In, PE etc. incidence and the death rate.Therefore, anticoagulant therapy has turned into current clinical prevention and treatment thrombotic disease
Core and basis, and the research and development of anticoagulant are also the focus of new drug development all the time, traditional anticoagulation, such as heparin leech
There is many side effects, such as haemolysis and hemorrhagic tendency in element, argatroban, warfarin, clopidogrel etc., using effect is simultaneously paid no attention to
Think.
The FXa factors (factor X activated, factor FXa) are a kind of serine proteases, positioned at blood coagulation
The upstream of cascade, the center of connection endogenous and exogenous activated pathway co-channel is in, FXa factor inhibitors can
Intrinsic coagulation is blocked also to suppress the generation of extrinsic coagulation.The FXa factors are the speed limit compositions of fibrin ferment generation, due in blood
The amplification of bio signal in liquid coagulation cascade course of reaction also be present, one FXa factor inhibitors molecule of estimation can suppress 138
The physiologic effect of individual prothrombin molecule, FXa factor inhibitors may be more more effective than thrombin inhibitor.The FXa factors are only simple
Promote blood coagulation, do not prevent platelet aggregation, without the side effect of thrombin inhibitor, therefore, FXa factor inhibitors turn near
One of focus that anticoagulation medicine is studied over year.
Since the razaxaban (visiing auspicious appropriate) of Bayer Bitterfeld GmbH pharmacy, have successively on the medicines such as Eliquis, Yi Dushaban
City, shellfish Qu Shaban, Tak-442 etc. enters clinical trial, and Tianjin Inst. of Materia Medica independent research knows that Fei Shaban pieces have also existed
Obtain clinical official written reply within 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 medicine, and it has a variety of pharmacological activity, wherein, low dosage using when have anti-blood small
The effect of plate aggregation, is generated so as to pre- preventing thrombosis, and the combination for razaxaban and other drugs in the prior art is carried out
A variety of trials, however with the combination of aspirin and failed, the two combination can not significantly improve anticoagulating active, increase on the contrary
Add the risk of bleeding.
The most common adverse reaction of aspirin is exactly gastrointestinal reaction, such as nausea, epigastric discomfort, vomiting.Orally
Aspirin can directly stimulate gastric mucosa so as to cause epigastric discomfort and nausea and vomiting, such as long-term use of aspirin, hold
It is easily caused the damage of stomach lining.
The content of the invention
The present invention relates to inhibitor of the razaxaban analog as the FXa factors shown in chemical formula (I), and its preparing
Purposes in anticoagulant, more specifically, the purposes in prevention or treatment thrombus or thrombosis drug is prepared.
It is an advantage of the invention to provide the compound of structure shown in following chemical formula (I), its is pharmaceutically useful
Salt：
Another object of the present invention is to, there is provided the preparation method of above-mentioned formula (I) compound is prepared, methods described includes
Following steps：
1) aspirin and chloride reagent effect generation 2- acetoxyl group chlorobenzoyl chlorides, 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- oxazolidinyls] phenyl] -3- morpholines ketone, 2- acetyloxy phenyls
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 compound shown in above-mentioned chemical formula (I) to prepare FXa factor inhibitors
The purposes of medicine, specifically as the purposes prepared in anticoagulation medicine, more particularly provide above-mentioned chemical formula (I)
Shown compound is as the purposes prepared in prevention and/or the purposes medicine for the treatment of thrombosis or embolism.By to people FXa's
Inhibitory action is tested, and the compounds of this invention shows excellent FXa inhibitory activity；Pass through the shadow to normal mouse APTT
The loud test of pesticide effectiveness, the compounds of this invention after 60min is administered can pole dramatically increase the APTT values of mouse, show good
Anticoagulation；By the development test to normal pharmacokinetics in rats, the compounds of this invention shows excellent medicine and moved
Feature is learned, it slowly releases aspirin in metabolic process, so as to enhance anticoagulant effect, and due to aspirin and change
Concentration peak and the non-concurrent appearance in blood of formula (I) compound, used so as to overcome razaxaban with aspirin combination
The side effect of the shortcomings that Shi Zengjia bleeding risks, also no aspirin often some stimulations stomach mucosa.
Embodiment
The present invention is described in further detail with test example with reference to embodiments, but not to the limit of the present invention
System, the equivalent substitution of all any this areas made according to the disclosure of invention, belongs to protection scope of the present invention.
The structure of compound by mass spectrum (MS) or nuclear magnetic resonance (1HNMR) determine.
Nuclear magnetic resonance (1HNMR) displacement (δ) is provided with the unit of hundred a ten thousandths (ppm)；Nuclear magnetic resonance (1HNMR survey)
Surely it is to use BrukerAVANCE-400 nuclear magnetic resonance spectrometers, measure solvent is deuterated DMSO, is inside designated as tetramethylsilane (TMS).
The measure of mass spectrum (MS) is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer：Therm, model： Finnigan
LCQ advantage MAX) carry out.
Column chromatography uses 200-300 mesh silica gel dress post.
In the case where the present invention does not provide specified otherwise, the reaction mentioned in the present invention is entered under anhydrous and oxygen-free
OK.
Refer to that temperature is between 20 DEG C -25 DEG C in the term " room temperature " of the present invention.
Raw material used in the present invention is commercially available prod, wherein (S) -2- ((2- oxos -3- (4- (3- oxomorpholin generations)
Phenyl) oxazolidine -5- ylmethyls) iso-indoles -1,3- diketone for synthesis razaxaban important intermediate, a variety of sides can be passed through
Method synthesizes, and repeats no more its preparation in this application.
Embodiment
Embodiment 1：The preparation of 2- acetoxyl groups-chlorobenzoyl chloride
Under the conditions of anhydrous and oxygen-free, 2- acetoxy-benzoics are added into dichloromethane, add thionyl chloride (1.5eq),
The DMF (1%) of catalytic amount, react at room temperature 3h.A small amount of reaction solution is taken, methanol is added, TLC monitoring reactions, treats
After reaction completely, reduced pressure at room temperature removes solvent, is washed with dichloromethane, and revolving removes solvent and (washed 2 times so that dichloro is sub- at room temperature
Sulfone removes clean), purified without further, be directly used in and react in next step.
Embodiment 2：The preparation of compound with chemical formula (I)
Under the conditions of anhydrous and oxygen-free, by (S) -2- ((2- oxos -3- (4- (3- oxomorpholin generations) phenyl) oxazolidine -5- Ji Jia
Base) iso-indoles -1,3- diketone (V, 1mmol) is dissolved in dichloromethane, add DIPEA (2.0eq), 2- second
Acyloxy-chlorobenzoyl chloride (IV, 1.5eq), room temperature reaction is overnight.TLC monitoring reactions, question response is complete, washes twice, dichloromethane
Alkane extracts, and column chromatographic isolation and purification, obtains the compound with chemical formula (I), is calculated with (V), 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：Influence to normal mouse APTT
1st, 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 project, be 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 values as the detection of this experiment
Mark, by studying influence of the compound of the embodiment of the present invention to mouse APTT, evaluates its anticoagulation.
2nd, experiment material
2.1 by reagent：
Positive drug：Razaxaban bulk drug, commercially available product, purity：99.3%；
By reagent：The compound of embodiment 2, white solid, purity：98.7%；
2.2 test equipment：
Sysmex CA7000 type full-automatic blood coagulation analyzers, produced by Japanese Sysmex companies；
Roche C501 automatic clinical chemistry analyzers, are produced by Roche；
Ophthalmic tweezers, gastric perfusion needle, mortar, vacuum blood collection tube, syringe etc..
2.3 experimental animal：
KM mouse, 28~30g of body weight, male, 60.Animal is raised after buying back in Animal House, adaptability observation at least 3
My god, quarantine qualified rear for testing.
3rd, test method
(1) it is grouped：Tested according to the packet of table 1, wherein every group of mouse is 20.
The experiment of table 1 packet and dosage regimen
(2) APTT is determined：Each group gives corresponding by reagent (blank group gives physiological saline), and after 1h is administered, eye socket takes blood
In the 0.5ml vacuum blood collection tubes containing sodium citrate, the APTT values of measure animal after blood sample are gathered.
4th, statistical method：
Counted using Excel, compare between multigroup and statistics comparison is carried out using the bilateral T methods of inspection.
5th, result of the test
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 |
6th, conclusion
The result of table 2 is shown, compared with blank group, after 1h is administered, the APTT values of positive group and each embodiment group dramatically increase,
Illustrate that razaxaban and the compound of the embodiment of the present invention 2 can dramatically increase the APTT values of mouse after 1h is administered；
Test example II：Inhibitory action of the compounds of this invention to people FXa
1st, test objective
Inhibitory action of the compound of the embodiment of the present invention to people FXa is studied, determines the IC50 suppressed to people FXa.
2nd, test material
2.1st, medicine：
Positive drug：Razaxaban bulk drug, purity：99.0%；
By reagent：The compound of embodiment 2, purity：98.2%.
2.2nd, test equipment：
EnVision multiple labelings detector (Perkin Elmer companies)；
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 solution：20mM Tris-HCl, 200mM NaCl, 2.5mM CaCl2, pH8.0.
2.3rd, test method：
(1) before the use, the compound of embodiment 2 and razaxaban are dissolved into 10mM with DMSO；
(2) each compounds of 10mM are taken, the compound gradient of 10 times of concentration is diluted to buffer solution, 40 μM are arrived
0.002048nM (5 times of dilutions)；
The compound solution of 6 μ L10 times concentration is added in (3) 384 orifice plates per hole.Final volume is 60 μ L, final compound concentration
Scope is from 4 μM to 0.0002048nM；
(4) 30 μ L people FXa enzymes (2nM), final concentration of 1nM are added per hole；
(5) 24 μ L people's FXa enzyme fluorescence chromophoric substrates (266.7 μM) of addition per hole, final concentration of 106.7 μM；
(6) gently shake 5 minutes, be then incubated at room temperature 30 minutes, lucifuge；
(7) 360/440nm fluorescence is read, and determines percent inhibition, using the 4Parameter in Xlfit softwares
Logistic Model calculate IC50。
3rd, result of the test：
Table 3：Inhibitory action of the embodiment compound to people FXa
| Group | Compound | IC50(nM) |
| To be measured group | The compound of embodiment 2 | 1.02 |
| Positive control | Razaxaban | 0.72 |
It was found from suppression test data of the compound of table 3 to people FXa, there is compound of the invention significant FXa to suppress
Activity, and positive drug razaxaban compare slightly poor, but are still enough to prepare anticoagulant as FXa inhibitor.
Test example III：Influence to rat suppository dry weight
Rat 60 is 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.5cm oneself silk for weighing is put into polyfluortetraethylene pipe
Line, polytetrafluoroethylene (PTFE) pipeline is full of with heparin-saline solution (50u/m1).When left neck is inserted in 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.Open artery clamp, middle clinopodium polycephalum after open blood flow 30min, the rapid silk thread that takes out is weighed, and can obtain wet weight of thrombus, 60 DEG C
Dry one hour, weighed after recovering room temperature, thrombus dry weight can be obtained.
The influence that the oral administration of compound of table 4 is formed to arteriovenous shunt thrombosis
Above-mentioned result of the test shows that the compound of the embodiment of the present invention 2 shows significant FXa inhibitory activity, blood coagulation activity
And excellent pharmacokinetic property, it can be used for preparing FXa factor inhibitors medicines, it is further to can be used for preparing anticoagulation
Thing, further it is 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 factors, in terms of antithrombotic
Show more excellent effect, thus it is speculated that when its reason is that compound is metabolized in vivo, amido link hydrolysis discharges aspirin institute
Cause.Razaxaban has bleeding risk when being combined with aspirin, but the aspirin of the application is discharged by compound hydrolysis
Go out, therefore its peak concentration staggers with the compound with chemical formula (I), has effectively evaded this risk, while also drop
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, for the ordinary skill in the art it is apparent that without departing from the present invention spirit or scope, can be to this hair
A variety of modification and transformations that bright compound, composition and method are carried out, therefore, the present invention include the modification and change to the present invention
Change, as long as in claim and its equivalent scope.
Claims (7)
1. compound and pharmaceutically acceptable salt shown in chemical formula (I)
2. the synthetic method of chemical formula (I) compound described in claim 1, it is reached by following reaction scheme,
3. including the pharmaceutical composition of chemical formula (I) compound described in claim 1, it includes the chemical formula of therapeutically effective amount
(I) compound and pharmaceutically acceptable auxiliary material.
4. purposes of the compound described in claim 1 in medicine is prepared.
5. purposes of the pharmaceutical composition described in claim 3 in medicine is prepared.
6. the purposes described in claim 4 or 5, it is characterised in that described medicine is FXa inhibitor.
7. the purposes described in claim 6, it is characterised in that described medicine is used to prevent and/or treat thromboembolia type disease
Disease or illness.
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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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| 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 true CN107827882A (en) | 2018-03-23 |
| CN107827882B CN107827882B (en) | 2019-12-03 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111333635A (en) * | 2020-04-16 | 2020-06-26 | 东南大学 | Rivaroxaban impurity reference substance and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050080081A1 (en) * | 2001-02-09 | 2005-04-14 | Alexander Straub | Substituted oxazolidinones and their use in the field of blood coagulation |
| 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 |
-
2017
- 2017-11-27 CN CN201711201460.0A patent/CN107827882B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050080081A1 (en) * | 2001-02-09 | 2005-04-14 | Alexander Straub | Substituted oxazolidinones and their use in the field of blood coagulation |
| 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 |
|---|
| MEGANATHAN CHANDRASEKARAN, ET AL.,: "Combined chemical feature-based assessment and Bayesian model studies to identify potential inhibitors for Factor Xa.", 《MED CHEM RES》 * |
| SUSANNE ROEHRIG, ET AL.,: "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.", 《J.MED.CHEM.》 * |
| 李慧等，: "噁唑烷酮醚类化合物的合成及其Xa因子抑制活性.", 《中国药科大学学报》 * |
| 高娜娜等，: "利伐沙班衍生物的合成及Xa因子抑制活性.", 《中国药科大学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111333635A (en) * | 2020-04-16 | 2020-06-26 | 东南大学 | Rivaroxaban impurity reference substance and preparation method thereof |
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