CN104693102A - Bishydrazide compound as well as preparation method and use thereof - Google Patents
Bishydrazide compound as well as preparation method and use thereof Download PDFInfo
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- CN104693102A CN104693102A CN201510079376.0A CN201510079376A CN104693102A CN 104693102 A CN104693102 A CN 104693102A CN 201510079376 A CN201510079376 A CN 201510079376A CN 104693102 A CN104693102 A CN 104693102A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 7
- 206010047249 Venous thrombosis Diseases 0.000 claims description 9
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 4
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 4
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 2
- 150000003949 imides Chemical class 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 abstract description 13
- 208000007536 Thrombosis Diseases 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 3
- 125000002560 nitrile group Chemical group 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000001035 drying Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 108010074860 Factor Xa Proteins 0.000 description 5
- 239000003146 anticoagulant agent Substances 0.000 description 5
- 229940127219 anticoagulant drug Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- 208000032843 Hemorrhage Diseases 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- 208000005189 Embolism Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- XVLGFRAACRIXFE-UHFFFAOYSA-N NNC(CCN(C(c(cc1)c2cc1C#N)=O)C2=O)=O Chemical compound NNC(CCN(C(c(cc1)c2cc1C#N)=O)C2=O)=O XVLGFRAACRIXFE-UHFFFAOYSA-N 0.000 description 2
- 208000001435 Thromboembolism Diseases 0.000 description 2
- 208000007814 Unstable Angina Diseases 0.000 description 2
- 206010000891 acute myocardial infarction Diseases 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 238000013016 damping Methods 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000001732 thrombotic effect Effects 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- OFJRNBWSFXEHSA-UHFFFAOYSA-N 2-(3-amino-1,2-benzoxazol-5-yl)-n-[4-[2-[(dimethylamino)methyl]imidazol-1-yl]-2-fluorophenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide Chemical compound CN(C)CC1=NC=CN1C(C=C1F)=CC=C1NC(=O)C1=CC(C(F)(F)F)=NN1C1=CC=C(ON=C2N)C2=C1 OFJRNBWSFXEHSA-UHFFFAOYSA-N 0.000 description 1
- KKJUPNGICOCCDW-UHFFFAOYSA-N 7-N,N-Dimethylamino-1,2,3,4,5-pentathiocyclooctane Chemical compound CN(C)C1CSSSSSC1 KKJUPNGICOCCDW-UHFFFAOYSA-N 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- 102000004411 Antithrombin III Human genes 0.000 description 1
- 108090000935 Antithrombin III Proteins 0.000 description 1
- 208000033386 Buerger disease Diseases 0.000 description 1
- PTMWASFYDIDRKY-UHFFFAOYSA-N CCOC(CCN(C(c(cc1)c2cc1C#N)=O)C2=O)=O Chemical compound CCOC(CCN(C(c(cc1)c2cc1C#N)=O)C2=O)=O PTMWASFYDIDRKY-UHFFFAOYSA-N 0.000 description 1
- 206010008088 Cerebral artery embolism Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- HGVDHZBSSITLCT-JLJPHGGASA-N Edoxaban Chemical compound N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=O)C(=O)NC1=CC=C(Cl)C=N1 HGVDHZBSSITLCT-JLJPHGGASA-N 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- 206010022562 Intermittent claudication Diseases 0.000 description 1
- QHDMHBFJCZJMHD-UHFFFAOYSA-N N#Cc(cc1)cc(C(N2)=O)c1C2=O Chemical compound N#Cc(cc1)cc(C(N2)=O)c1C2=O QHDMHBFJCZJMHD-UHFFFAOYSA-N 0.000 description 1
- QCEGOCIIRYTCQH-UHFFFAOYSA-N O=S(c1ccc(cccc2)c2c1)=O Chemical compound O=S(c1ccc(cccc2)c2c1)=O QCEGOCIIRYTCQH-UHFFFAOYSA-N 0.000 description 1
- 235000019082 Osmanthus Nutrition 0.000 description 1
- 241000333181 Osmanthus Species 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 208000006193 Pulmonary infarction Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 206010043540 Thromboangiitis obliterans Diseases 0.000 description 1
- 108010064129 Thrombogen Proteins 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229960005348 antithrombin iii Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 238000007887 coronary angioplasty Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229960000622 edoxaban Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 210000001624 hip Anatomy 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 208000021156 intermittent vascular claudication Diseases 0.000 description 1
- 201000010849 intracranial embolism Diseases 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000007575 pulmonary infarction Effects 0.000 description 1
- 229950010535 razaxaban Drugs 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 230000002792 vascular Effects 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a bishydrazide compound 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 a nitrile group 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 (1.72g, 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=273 ([M+H]
+).
B. the synthesis of compound IV-1
Compound III-1 (1.36g, 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=259 ([M+H]
+).
C. the synthesis of Compound I
Compound IV-1 (0.52g, 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=449 ([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 | 3.0 |
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 |
|---|---|---|---|
| CN201510079376.0A CN104693102A (en) | 2015-02-13 | 2015-02-13 | Bishydrazide compound as well as preparation method and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510079376.0A CN104693102A (en) | 2015-02-13 | 2015-02-13 | Bishydrazide compound as well as preparation method and use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104693102A true CN104693102A (en) | 2015-06-10 |
Family
ID=53340699
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510079376.0A Pending CN104693102A (en) | 2015-02-13 | 2015-02-13 | Bishydrazide compound as well as preparation method and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104693102A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0478328A1 (en) * | 1990-09-27 | 1992-04-01 | Merck & Co. Inc. | Novel fibrinogen receptor antagonists |
| WO2000071509A1 (en) * | 1999-05-24 | 2000-11-30 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
| CN101654427A (en) * | 2008-08-19 | 2010-02-24 | 信谊药厂 | Anticoagulant compound, composition and application thereof |
-
2015
- 2015-02-13 CN CN201510079376.0A patent/CN104693102A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0478328A1 (en) * | 1990-09-27 | 1992-04-01 | Merck & Co. Inc. | Novel fibrinogen receptor antagonists |
| WO2000071509A1 (en) * | 1999-05-24 | 2000-11-30 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
| CN101654427A (en) * | 2008-08-19 | 2010-02-24 | 信谊药厂 | Anticoagulant compound, composition and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| MARIE-ROSE ABDO等: "Brucella suis histidinol dehydrogenase: Synthesis and inhibition studies of substituted N-L-histidinylphenylsulfonyl hydrazide", 《JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY》 * |
| 曾向潮等: "微波辐射法合成β-酞酰亚胺基丙酸酯（丙腈）", 《化学试剂》 * |
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Application publication date: 20150610 |