CN104693101A - Bishydrazide derivative as well as preparation method and use thereof - Google Patents
Bishydrazide derivative as well as preparation method and use thereof Download PDFInfo
- Publication number
- CN104693101A CN104693101A CN201510079358.2A CN201510079358A CN104693101A CN 104693101 A CN104693101 A CN 104693101A CN 201510079358 A CN201510079358 A CN 201510079358A CN 104693101 A CN104693101 A CN 104693101A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- formula
- fxa inhibitor
- present
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- ZIJRDDPNEXIVCF-UHFFFAOYSA-N Nc(cc1C(N2CCC(NN)=O)=O)ccc1C2=O Chemical compound Nc(cc1C(N2CCC(NN)=O)=O)ccc1C2=O ZIJRDDPNEXIVCF-UHFFFAOYSA-N 0.000 description 2
- MTPRYXQYDKSDLH-UHFFFAOYSA-N CCOC(CCN(C(c(c1c2)ccc2N)=O)C1=O)=O Chemical compound CCOC(CCN(C(c(c1c2)ccc2N)=O)C1=O)=O MTPRYXQYDKSDLH-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N Nc(cc1C(N2)=O)ccc1C2=O Chemical compound Nc(cc1C(N2)=O)ccc1C2=O PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- OUMUQKMAVALVQZ-UHFFFAOYSA-N Nc(cc1C(N2CCC(NNS(c3ccc(cccc4)c4c3)(=O)=O)=O)=O)ccc1C2=O Chemical compound Nc(cc1C(N2CCC(NNS(c3ccc(cccc4)c4c3)(=O)=O)=O)=O)ccc1C2=O OUMUQKMAVALVQZ-UHFFFAOYSA-N 0.000 description 1
- LTSBKUWFXANFCU-UHFFFAOYSA-N OS(c1cc(cccc2)c2cc1)=O Chemical compound OS(c1cc(cccc2)c2cc1)=O LTSBKUWFXANFCU-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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 derivative as well as a preparation method and use thereof, relates to the field of venous thrombotic disease related drugs and particularly relates to an FXa inhibitor containing an amino substituted 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.
Description
Technical field
The present invention relates to the pharmaceutical field of Venous Thrombosis treatment.More particularly, the present invention relates to Venous Thrombosis medicative a kind of FXa inhibitor, its preparation method 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 a kind of FXa inhibitor containing bishydrazide structure of novel structure, 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 formula I.
Another object of the present invention is to provide the method that preparation has the compound of formula I.
The compound that another object of the present invention is to provide containing 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 formula I has following structural formula:
Formula I of the present invention 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.
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 formula I of the present invention is verified by receptor binding assays.
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 formula I 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
A. the synthesis of compound III-1
Compound II per-1 (1.62g, 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=263 ([M+H]
+).
B. the synthesis of compound IV-1
Compound III-1 (1.31g, 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=249 ([M+H]
+).
C. the synthesis of Compound I
Compound IV-1 (0.50g, 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, white solid, ESI-MS, m/z=439 ([M+H]
+).
the synthesis of embodiment 2 reference compound D-1
Compound D-1 is all the compound (not yet open by the applying date) that the present inventor designs in research process.
A. the synthesis of compound III-2
Compound II per-2 (1.47g, 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-2, white solid, ESI-MS, m/z=248 ([M+H]
+).
B. the synthesis of compound IV-2
Compound III-2 (1.23g, 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-2, white solid, ESI-MS, m/z=234 ([M+H]
+).
C. the synthesis of Compound D-1
Compound IV-2 (0.47g, 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 D-1, white solid, ESI-MS, m/z=424 ([M+H]
+).
embodiment 3 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) |
| Reference compound D-1 (embodiment 2) | 6.7 |
| Compound I-1 | 3.5 |
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 (3)
1. there is the compound of formula I structure,
2. synthesize the method for the compound of formula I described in claim 1:
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.
3. the application of formula I described in claim 1 in preparation treatment Venous Thrombosis medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510079358.2A CN104693101A (en) | 2015-02-13 | 2015-02-13 | Bishydrazide derivative as well as preparation method and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510079358.2A CN104693101A (en) | 2015-02-13 | 2015-02-13 | Bishydrazide derivative as well as preparation method and use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104693101A true CN104693101A (en) | 2015-06-10 |
Family
ID=53340698
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510079358.2A Pending CN104693101A (en) | 2015-02-13 | 2015-02-13 | Bishydrazide derivative as well as preparation method and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104693101A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000071509A1 (en) * | 1999-05-24 | 2000-11-30 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
| CN1518447A (en) * | 2001-04-23 | 2004-08-04 | �������Ǵ�ѧר������� | Synthesis and evaluation of novel phthalimide mimics as anti-angiogenic agents |
| CN101654427A (en) * | 2008-08-19 | 2010-02-24 | 信谊药厂 | Anticoagulant compound, composition and application thereof |
| EP2418200A1 (en) * | 2009-04-06 | 2012-02-15 | Ems S. A. | Phthalimide derivatives of non-steroidal anti-inflammatory compounds and/or tnf- modulators, method for producing same, pharmaceutical compositions containing same and uses thereof for the treatment of inflammatory diseases |
-
2015
- 2015-02-13 CN CN201510079358.2A patent/CN104693101A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000071509A1 (en) * | 1999-05-24 | 2000-11-30 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
| CN1518447A (en) * | 2001-04-23 | 2004-08-04 | �������Ǵ�ѧר������� | Synthesis and evaluation of novel phthalimide mimics as anti-angiogenic agents |
| CN101654427A (en) * | 2008-08-19 | 2010-02-24 | 信谊药厂 | Anticoagulant compound, composition and application thereof |
| EP2418200A1 (en) * | 2009-04-06 | 2012-02-15 | Ems S. A. | Phthalimide derivatives of non-steroidal anti-inflammatory compounds and/or tnf- modulators, method for producing same, pharmaceutical compositions containing same and uses thereof for the treatment of inflammatory diseases |
Non-Patent Citations (3)
| 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》 * |
| 曾向潮: "微波辐射法合成β-酞酰亚胺基丙酸酯(丙腈)", 《化学试剂》 * |
| 高伟 等: "双酰肼类化合物的应用研究进展", 《化工进展》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| BR9612423B1 (en) | compound of substituted n - [(aminoimino-methyl or amino-methyl) phenyl] propyl amides, and, pharmaceutical composition. | |
| US20040082786A1 (en) | Piperazine based inhibitors of factor xa | |
| CN104693101A (en) | Bishydrazide derivative as well as preparation method and use thereof | |
| CN104693102A (en) | Bishydrazide compound as well as preparation method and use thereof | |
| CN104693099A (en) | Bishydrazide and naphthyl structure containing compound and use thereof | |
| CN104693103A (en) | Bishydrazide compound and use thereof | |
| CN104693100A (en) | Bishydrazide and amidonaphthalene structure containing compound and use thereof | |
| CN104693098A (en) | Bishydrazide and nitro-naphthyl structure containing compound as well as preparation method and use thereof | |
| CN104672234B (en) | One class is containing FXa inhibitor, the preparation method and its usage of biamide structure | |
| CN104672235B (en) | One class contains FXa inhibitor of bisamide base and alkoxyphenyl radical structure and uses thereof | |
| CN104693093A (en) | Bishydrazide FXa inhibitor and preparation method and use thereof | |
| CN104610258B (en) | FXa inhibitor, the preparation method and its usage of one class amide containing and methoxy benzene structure | |
| CN104672236B (en) | One class contains FXa inhibitor of bisamide base and halogeno-benzene structure and uses thereof | |
| CN104710341A (en) | Compound containing bishydrazide and naphthyl structure, as well as preparation method and application of compound | |
| CN104693095A (en) | Bishydrazide FXa inhibitor and use thereof | |
| CN104693096A (en) | Bishydrazide and naphthyl structure containing compound as well as preparation method and use thereof | |
| CN104693097A (en) | Bishydrazide and alkoxy-naphthyl structure containing compound as well as preparation method and use thereof | |
| CN104610260B (en) | FXa inhibitor, the preparation method and its usage of one class amide containing and nitrogen heterocyclic structure | |
| CN104693094A (en) | Bishydrazide FXa inhibitor as well as preparation method and use thereof | |
| CN104557927B (en) | A kind of coagulation factor xa inhibitors containing bicyclic amide structure and purposes thereof | |
| CN104557929B (en) | One class contains coagulation factor xa inhibitors and the purposes thereof of bicyclic amide structure | |
| CN104557930B (en) | A kind of containing bicyclic amide structure coagulation factor xa inhibitors and purposes thereof | |
| US20040077690A1 (en) | Quaternary amidino based inhibitors of factor xa | |
| CN104610257B (en) | The FXa inhibitor of one class amide containing structure, preparation method and its usage | |
| CN104610259B (en) | The FXa inhibitor of amide containing and nitrogen heterocyclic structure, preparation method and its usage |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150610 |