CN104672234B - One class is containing FXa inhibitor, the preparation method and its usage of biamide structure - Google Patents
One class is containing FXa inhibitor, the preparation method and its usage of biamide structure Download PDFInfo
- Publication number
- CN104672234B CN104672234B CN201510083413.5A CN201510083413A CN104672234B CN 104672234 B CN104672234 B CN 104672234B CN 201510083413 A CN201510083413 A CN 201510083413A CN 104672234 B CN104672234 B CN 104672234B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- obtains
- general formula
- fxa inhibitor
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000003112 inhibitor Substances 0.000 title abstract description 12
- 206010047249 Venous thrombosis Diseases 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 67
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 10
- 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 10
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 claims description 6
- 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 5
- 238000000034 method Methods 0.000 claims description 4
- 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
- 238000010306 acid treatment Methods 0.000 claims description 2
- 238000007259 addition reaction Methods 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 238000001035 drying Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 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
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- 208000007536 Thrombosis Diseases 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 208000032843 Hemorrhage Diseases 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 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 2
- 208000005189 Embolism Diseases 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
- UICWSWIMNYSQKK-UHFFFAOYSA-N benzhydrylbenzene;hydrochloride Chemical compound Cl.C1=CC=CC=C1C(C=1C=CC=CC=1)C1=CC=CC=C1 UICWSWIMNYSQKK-UHFFFAOYSA-N 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
- 229960000622 edoxaban Drugs 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000001732 thrombotic effect Effects 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- 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
- 206010008088 Cerebral artery embolism Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- 206010022562 Intermittent claudication Diseases 0.000 description 1
- 235000019082 Osmanthus Nutrition 0.000 description 1
- 241000333181 Osmanthus Species 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 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
- 229940079593 drug 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
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The present invention relates to the pharmaceutical field relevant to Venous Thrombosis.Specifically, the present invention relates to a class contain FXa inhibitor, its preparation method of biamide structure and preparing the application in Venous Thrombosis medicine.
wherein, R is selected from C
1-C
3alkyl, C
3-C
6cycloalkyl.
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 biamide 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 biamide 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
3alkyl, C
3-C
6cycloalkyl.
More preferably the compound of general formula I has following structure,
Compound of Formula I of the present invention is synthesized by following route:
Compound II per can obtain according to US5468742 (1995).
Compound II per reacts with triphenylmethyl chloride (TrCl) in the presence of a base, obtains compound III; There is addition reaction in compound III and IV, obtains compound V; Trityl is sloughed in compound V acid treatment, obtains compound VI; There is lower and compound VI I condensation at DCC (N, N'-dicyclohexyl carbodiimide) in compound VI, 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
Compound II per (1.26g, 10mmol) and triethylamine (3.04g, 30mmol) are dissolved in the DMF of 10mL drying, and ice-water bath cooling is lower stirs, and slowly drips by Triphenyl methane chloride 99 (TrCl; 3.07g, 11mmol) and 10mL drying DMF preparation solution.After dropwising, gained reaction mixture at room temperature stirs 3 hours, and TLC shows reaction to be completed.Reaction mixture pours in 120mL frozen water, 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, white solid, ESI-MS, m/z=369 ([M+H]
+).
B. the synthesis of compound V-1
Compound III (2.21g, 6mmol) and compound IV-1 (1.09g, 6mmol) are dissolved in the DMF of 20mL drying, stir, at N
2the lower backflow of protection 1 hour, TLC detection reaction completes.Reaction mixture pours in 120mL frozen water, 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 V-1, white solid, ESI-MS, m/z=551 ([M+H]
+).
C. the synthesis of compound VI-1
Compound V-1 (2.20g, 4mmol) is dissolved in 20mL methyl alcohol, and stirred at ambient temperature adds 1mL concentrated hydrochloric acid, continues stirring 5 hours under room temperature, and TLC checks and finds that reaction completes.Reaction mixture pours in 120mL frozen water, with saturated NaHCO
3solution regulates pH=8, 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 VI-1, white solid, ESI-MS, m/z=308 ([M+H]
+).
D. the synthesis of Compound I-1
Compound VI-1 (0.62g, 2mmol) and compound VI I-1 (0.27g, 2mmol) are dissolved in the THF of 8mL drying, stirred at ambient temperature, add DCC (0.62g, 3mmol) and DMAP (DMAP; 0.1g), then room temperature for overnight, TLC detection reaction completes.Reaction mixture pours in 100mL frozen water, CH
2cl
2(50mL × 3) extract, and merge extraction phase, use 3% 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=426 ([M+H]
+).
embodiment 2-8
With reference to the method for embodiment 1, synthesize compound listed in Table.
the synthesis of embodiment 7 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
Compound II per (1.26g, 10mmol) and triethylamine (3.04g, 30mmol) are dissolved in the DMF of 10mL drying, and ice-water bath cooling is lower stirs, and slowly drips by Triphenyl methane chloride 99 (TrCl; 3.07g, 11mmol) and 10mL drying DMF preparation solution.After dropwising, gained reaction mixture at room temperature stirs 3 hours, and TLC shows reaction to be completed.Reaction mixture pours in 120mL frozen water, 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, white solid, ESI-MS, m/z=369 ([M+H]
+).
B. the synthesis of compound V-7
Compound III (2.21g, 6mmol) and compound IV-7 (0.88g, 6mmol) are dissolved in the DMF of 20mL drying, stir, at N
2the lower backflow of protection 1 hour, TLC detection reaction completes.Reaction mixture pours in 120mL frozen water, 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 V-7, white solid, ESI-MS, m/z=516 ([M+H]
+).
C. the synthesis of compound VI-7
Compound V-7 (2.06g, 4mmol) is dissolved in 20mL methyl alcohol, and stirred at ambient temperature adds 1mL concentrated hydrochloric acid, continues stirring 5 hours under room temperature, and TLC checks and finds that reaction completes.Reaction mixture pours in 120mL frozen water, with saturated NaHCO
3solution regulates pH=8, 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 VI-7, white solid, ESI-MS, m/z=274 ([M+H]
+).
D. the synthesis of Compound D-1
Compound VI-7 (0.55g, 2mmol) and compound VI I-7 (0.24g, 2mmol) are dissolved in the THF of 8mL drying, stirred at ambient temperature, add DCC (0.62g, 3mmol) and DMAP (DMAP; 0.1g), then room temperature for overnight, TLC detection reaction completes.Reaction mixture pours in 100mL frozen water, CH
2cl
2(50mL × 3) extract, and merge extraction phase, use 3% 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=378 ([M+H]
+).
embodiment 8 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 (100mMTris, 200mM Repone K, 0.2%BSA, pH7.4) (40 μ l) and 0.0625U/mL people FXa (EnzymeResearchLabolatories, 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 (ChromogenixCo.), 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 | 4.0 |
| Reference compound D-1 | 7.8 |
| Compound I-1 | 2.1 |
| Compound I-2 | 2.6 |
| Compound I-3 | 5.5 |
| Compound I-4 | 2.8 |
| Compound I-5 | 4.1 |
| Compound I-6 | 3.3 |
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
3alkyl, C
3-C
6cycloalkyl.
2. the compound with general formula I that claim 1 defines, is selected from following compounds,
3. synthesize arbitrary the defined method with the compound of general formula I of claim 1-2:
Compound II per reacts with triphenylmethyl chloride (TrCl) in the presence of a base, obtains compound III; There is addition reaction in compound III and IV, obtains compound V; Trityl is sloughed in compound V acid treatment, obtains compound VI; There is lower and compound VI I condensation at N, N'-dicyclohexyl carbodiimide in compound VI, obtains Compound I; Wherein, the definition of R as arbitrary in claim 1-2 as described in.
4. the application of the compound with general formula I that one of claim 1-2 defines in preparation treatment Venous Thrombosis medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510083413.5A CN104672234B (en) | 2015-02-14 | 2015-02-14 | One class is containing FXa inhibitor, the preparation method and its usage of biamide structure |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510083413.5A CN104672234B (en) | 2015-02-14 | 2015-02-14 | One class is containing FXa inhibitor, the preparation method and its usage of biamide structure |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104672234A CN104672234A (en) | 2015-06-03 |
| CN104672234B true CN104672234B (en) | 2016-01-27 |
Family
ID=53307869
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510083413.5A Active CN104672234B (en) | 2015-02-14 | 2015-02-14 | One class is containing FXa inhibitor, the preparation method and its usage of biamide structure |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104672234B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19735198A1 (en) * | 1997-08-14 | 1999-02-18 | Bayer Ag | Optical resolution of cis- or trans-pyrrolo:piperidine derivatives |
| CN103242310A (en) * | 2012-02-10 | 2013-08-14 | 苏州迈泰生物技术有限公司 | Pyrazolo pyridone compound and its application in preparation of anticoagulant |
-
2015
- 2015-02-14 CN CN201510083413.5A patent/CN104672234B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN104672234A (en) | 2015-06-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2017071479A1 (en) | Glutamine acyl cyclase inhibitor | |
| CN106831866A (en) | One aryl oxidized phosphine P2Y12 receptor antagonists of class alcoxyl thiophene and application thereof | |
| CN104672234B (en) | One class is containing FXa inhibitor, the preparation method and its usage of biamide structure | |
| CN104672236B (en) | One class contains FXa inhibitor of bisamide base and halogeno-benzene structure and uses thereof | |
| CN104672235B (en) | One class contains FXa inhibitor of bisamide base and alkoxyphenyl radical structure and uses thereof | |
| CN104610258B (en) | FXa inhibitor, the preparation method and its usage of one class amide containing and methoxy benzene structure | |
| CN104610260B (en) | FXa inhibitor, the preparation method and its usage of one class amide containing and nitrogen heterocyclic structure | |
| CN104592227B (en) | The FXa inhibitor of one class amide containing and halogeno-benzene structure, preparation method and its usage | |
| CN104610257B (en) | The FXa inhibitor of one class amide containing structure, preparation method and its usage | |
| CN104557927B (en) | A kind of coagulation factor xa inhibitors containing bicyclic amide structure and purposes thereof | |
| CN104610259B (en) | The FXa inhibitor of amide containing and nitrogen heterocyclic structure, preparation method and its usage | |
| CN104557930B (en) | A kind of containing bicyclic amide structure coagulation factor xa inhibitors and purposes thereof | |
| CN104557929B (en) | One class contains coagulation factor xa inhibitors and the purposes thereof of bicyclic amide structure | |
| CN104860942A (en) | FXa inhibitor containing bisamide radical and nitrobenzophenone structure and application thereof | |
| CN104725374A (en) | FXa inhibitor containing bisamide and cyanobenzene structure and application thereof | |
| CN104650082B (en) | One class coagulation factor xa inhibitors, preparation method and its usage | |
| CN104650081B (en) | Coagulation factor xa inhibitors, preparation method and its usage | |
| CN104557928B (en) | A kind of containing bicyclic amide structure coagulation factor xa inhibitors, Its Preparation Method And Use | |
| CN104710341A (en) | Compound containing bishydrazide and naphthyl structure, as well as preparation method and application of compound | |
| CN104693094A (en) | Bishydrazide FXa inhibitor 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 | |
| CN104693093A (en) | Bishydrazide FXa inhibitor and preparation method and use thereof | |
| CN104693102A (en) | Bishydrazide compound as well as preparation method and use thereof | |
| CN104693095A (en) | Bishydrazide FXa inhibitor and use thereof | |
| CN104693098A (en) | Bishydrazide and nitro-naphthyl structure containing compound as well as preparation method and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: FXa inhibitors containing bisamide structure as well as preparation method and application thereof Effective date of registration: 20170816 Granted publication date: 20160127 Pledgee: Guangdong Nanhai Rural Commercial Bank branch branch of Limited by Share Ltd Pledgor: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY CO., LTD. Registration number: 2017990000756 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20190604 Granted publication date: 20160127 Pledgee: Guangdong Nanhai Rural Commercial Bank branch branch of Limited by Share Ltd Pledgor: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY CO., LTD. Registration number: 2017990000756 |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20191114 Address after: 225321 Industrial Park, Dasi Town, Gaogang District, Taizhou City, Jiangsu Province Patentee after: Luan Yong Address before: Chancheng district has 528000 Taiwan public in Guangdong province Foshan City No. 32 first floor 1636, shop No. 1637 Patentee before: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY CO., LTD. |
|
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: Jiangsu Housing City Construction Engineering Quality Inspection Co., Ltd., No. 118, Xingtang Road, Fenghuang street, medical high tech Zone, Taizhou City, Jiangsu Province Patentee after: Luan Yong Address before: 225321 Industrial Park, Dasi Town, Gaogang District, Taizhou City, Jiangsu Province Patentee before: Luan Yong |