CN104693095A - Bishydrazide FXa inhibitor and use thereof - Google Patents
Bishydrazide FXa inhibitor and use thereof Download PDFInfo
- Publication number
- CN104693095A CN104693095A CN201510079207.7A CN201510079207A CN104693095A CN 104693095 A CN104693095 A CN 104693095A CN 201510079207 A CN201510079207 A CN 201510079207A CN 104693095 A CN104693095 A CN 104693095A
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- China
- Prior art keywords
- compound
- fxa inhibitor
- bishydrazide
- formula
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
Abstract
The invention discloses a bishydrazide FXa inhibitor and use thereof, relates to the field of venous thrombotic disease related drugs and particularly relates to an FXa inhibitor containing a bishydrazide structure, a preparation method of the FXa inhibitor and an application of the FXa inhibitor in preparation of drugs for treating venous thrombotic diseases. The FXa inhibitor has a structure represented by a formula shown in descriptions, wherein R is selected from C1-C4 alkyl and C3-C8 cycloalkyl.
Description
Technical field
The present invention relates to the pharmaceutical field of Venous Thrombosis treatment.More particularly, the present invention relates to FXa inhibitor, its preparation method of the medicative class of Venous Thrombosis containing bishydrazide structure, and the purposes in pharmacy.
Background technology
The deterioration of clotting ability is unstable angina pectoris, brain osmanthus plug, cerebral embolism, cardiac muscle carry plug, inaccessible again or extracorporeal circulation after thrombosis after lung infraction, pulmonary infarction, thromboangiitis obliterans, venous thrombosis, disseminated intravascular coagulation, replacing valve, revascularization time thrombotic important factor.In Arterial system, abnormal thrombus is formed main relevant with coronary artery, the cerebrovascular and peripheral blood vessel, close that relevant disease mainly comprises Acute Myocardial Infarction (AMI), unstable angina, thromboembolism, the acute vascular relevant with Post-percutaneous Transluminal Coronary Angioplasty (PTCA) with thromboembolism treatment close with the thrombosis of these blood vessels, transient ischemic attack, apoplexy, intermittent claudication and coronary artery bypass graft surgery (CABG) or peripheral arterial bypass graft.For vein blood vessel, pathologic thrombus forms the veins of lower extremity after often occurring in belly, knee joint and Hip operation (venous thrombosis, DVT).DVT also makes patient be among the highly dangerous of easily trouble pulmonary thromboembolism.So need to develop excellent anti-coagulant, it is little that this anti-coagulant has excellent dose response, time length long, hemorrhage danger, is almost free from side effects, and namely use and orally also can reach abundant effect very soon.
According to the research of the mechanism of action to various anti-coagulant, coagulation factor xa inhibitors (FXa inhibitor) is considered to good anti-coagulant.Factor Xa is second from the bottom kind of enzyme in blood coagulation chain.The restraining effect of factor Xa obtains by directly forming complex body between this inhibitor and enzyme, and therefore this enzyme and blood plasma cofactor Antithrombin III have nothing to do.Effective factor Xa restraining effect is used this compound to realize by oral administration, venoclysis continuously, bolus injection intravenously administrable or any other parental routes, can obtain the required effect stoping factor Xa to bring out thrombogen formation zymoplasm thus.Another advantage of FXa inhibitor is that in effective dose in thrombotic model and experimental Hemorrhage Model, the dosage of time expand has very big difference.By this this test-results, can think that FXa inhibitor is the anti-coagulant that hemorrhage risk is less.Report the multiple compound being used as FXa inhibitor, and have many approval clinically, as razaxaban etc.
The invention discloses the FXa inhibitor containing bishydrazide structure of a class formation novelty, these compounds can be used for the medicine preparing treatment Venous Thrombosis.
Summary of the invention
An object of the present invention is to provide a kind of FXa inhibitor with the excellent activity of general formula I.
Another object of the present invention is to provide the method that preparation has the compound of general formula I.
The compound that another object of the present invention is to provide containing general formula I is treating the application in Venous Thrombosis as effective constituent.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The compound that the present invention has general formula I has following structural formula:
Wherein, R is selected from C
1-C
4alkyl, C
3-C
8cycloalkyl.
The compound of preferred formula (I) has following structure,
General formula of the present invention (I) compound is synthesized by following route:
Compound II per is first obtained by reacting its corresponding imide sylvite with KOH, and the latter to ethyl propenoate addition, obtains compound III again; Compound III and hydrazine hydrate are obtained by reacting IV; Compound IV is reacted with SULPHURYL CHLORIDE V in the presence of a base, obtains Compound I; Wherein, the definition of R as previously mentioned.
Compound of Formula I of the present invention has the restraining effect of FXa, can be used as effective constituent for the preparation of phlebothrombosis medicine.The activity of compound of Formula I of the present invention is verified by receptor binding assays.
Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 1mg-1000mg/ people, is divided into once or administration for several times.The actual dosage taking compound of Formula I of the present invention can be decided according to relevant situation by doctor.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.
the synthesis of embodiment 1 Compound I-1
A. the synthesis of compound III-1
Compound II per-1 (1.77g, 10mmol) be dissolved in 10mL DMSO, stirred at ambient temperature, slowly add solid KOH (0.67g, 12mmol), continue to stir 10min, then ethyl propenoate (1.20g is added, 12mmol), reaction mixture then at room temperature stirs 30min, and TLC shows reaction to be completed.Reaction mixture pours in 150mL frozen water, stirs, CH
2cl
2(50mL × 3) extract, and merge extraction phase, use salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound III-1, white solid, ESI-MS, m/z=278 ([M+H]
+).
B. the synthesis of compound IV-1
Compound III-1 (1.39g, 5mmol) is dissolved in 10mL dehydrated alcohol, stirred at ambient temperature, and add 80% hydrazine hydrate (0.38g, 6mmol), reaction mixture then at room temperature stirs 30min, and TLC shows reaction to be completed.Reaction mixture pours in 100mL frozen water, stirs, CH
2cl
2(50mL × 3) extract, and merge extraction phase, use salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains compound IV-1, white solid, ESI-MS, m/z=264 ([M+H]
+).
C. the synthesis of Compound I-1
Compound IV-1 (0.53g, 2mmol) and triethylamine (0.61g, 6mmol) are dissolved in the CH of 5mL drying
2cl
2in, ice-water bath cooling is lower stirs, and slowly drips the CH by compound V-1 (0.45g, 2mmol) and 2mL drying
2cl
2the solution of preparation, dropwises rear reaction mixture and then at room temperature stirs 1h, and TLC shows reaction to be completed.Reaction mixture pours in 100mL frozen water, stirs, CH
2cl
2(50mL × 3) extract, and merge extraction phase, use 1% dilute hydrochloric acid and salt water washing successively, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and the resistates obtained uses column chromatography purification, obtains Compound I-1, white solid, ESI-MS, m/z=454 ([M+H]
+).
embodiment 2-4
With reference to embodiment 1 operation steps, synthesize compound listed in Table.
embodiment 5 Compound ira vitro is to the inhibition test of FXa
By the 5%DMSO solution (10 μ L) (its concentration progressively suitably sets) of embodiment compound to be measured and positive drug EDOXABAN, Tris damping fluid (100mM Tris, 200mM Repone K, 0.2%BSA, pH 7.4) (40 μ l) and 0.0625U/mL people FXa (Enzyme Research Labolatories, Inc., the hole that (10 μ l) puts into 96 hole minitype plates is respectively diluted with Tris buffer solution, add 750 μMs of aqueous solution (40 μ l) of S2222 (Chromogenix Co.), to measure the absorbancy at 405nm under 10 minutes room temperatures, thus measure absorbancy increase (Δ OD/min).As negative control, replace test compound with Tris damping fluid.
According to formula below, on the ordinate zou that the percent inhibition (%) when test compound initial concentration and test compound final concn is painted on the orthogonal probability tables of logarithm respectively and X-coordinate, to determine 50% suppression dosage (IC
50value).
Percent inhibition (%)=[1-(the Δ OD/min of sample)/(contrast Δ OD/min)] × 100
Test result sees the following form.
| Compound | IC 50(nM) |
| Edoxaban | 3.8 |
| Compound I-1 | 3.9 |
| Compound I-2 | 3.1 |
| Compound I-3 | 4.7 |
| Compound I-4 | 4.3 |
As can be seen from upper table result, compound of the present invention is good FXa inhibitor, can as the medicine of preparation treatment Venous Thrombosis.
Claims (4)
1. there is the compound of general formula I,
Wherein, R is selected from C
1-C
4alkyl, C
3-C
8cycloalkyl.
2. the compound of Formula I that defines of claim 1, is selected from:
3. synthesize the method for the compound of arbitrary the defined general formula I of claim 1-2:
Compound II per is first obtained by reacting its corresponding imide sylvite with KOH, and the latter to ethyl propenoate addition, obtains compound III again; Compound III and hydrazine hydrate are obtained by reacting IV; Compound IV is reacted with SULPHURYL CHLORIDE V in the presence of a base, obtains Compound I; Wherein, the definition of R as arbitrary in claim 1-2 as described in.
4. the compound of Formula I that one of claim 1-2 defines is preparing the application in treatment Venous Thrombosis medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510079207.7A CN104693095A (en) | 2015-02-13 | 2015-02-13 | Bishydrazide FXa inhibitor and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510079207.7A CN104693095A (en) | 2015-02-13 | 2015-02-13 | Bishydrazide FXa inhibitor and use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104693095A true CN104693095A (en) | 2015-06-10 |
Family
ID=53340692
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510079207.7A Pending CN104693095A (en) | 2015-02-13 | 2015-02-13 | Bishydrazide FXa inhibitor and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104693095A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000071509A1 (en) * | 1999-05-24 | 2000-11-30 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
| WO2011123468A1 (en) * | 2010-03-29 | 2011-10-06 | Alnylam Pharmaceuticals, Inc. | Sirna therapy for transthyretin (ttr) related ocular amyloidosis |
-
2015
- 2015-02-13 CN CN201510079207.7A patent/CN104693095A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000071509A1 (en) * | 1999-05-24 | 2000-11-30 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
| WO2011123468A1 (en) * | 2010-03-29 | 2011-10-06 | Alnylam Pharmaceuticals, Inc. | Sirna therapy for transthyretin (ttr) related ocular amyloidosis |
Non-Patent Citations (1)
| Title |
|---|
| MARIE-ROSE ABDO ET AL.: "Brucella suis histidinol dehydrogenase: Synthesis and inhibition studies of substituted N-L-histidinylphenylsulfonyl hydrazide", 《JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY》 * |
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Application publication date: 20150610 |
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