CN106800524A - Compound, preparation method and its usage of one class containing bishydrazide and naphthyl structure - Google Patents
Compound, preparation method and its usage of one class containing bishydrazide and naphthyl structure Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims description 53
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 125000001624 naphthyl group Chemical group 0.000 title abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 8
- 206010047249 Venous thrombosis Diseases 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 10
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- 238000000034 method Methods 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
- 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 3
- 239000001103 potassium chloride Substances 0.000 claims description 3
- 235000011164 potassium chloride Nutrition 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 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 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- 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
- 239000002253 acid Substances 0.000 claims description 2
- 230000036571 hydration Effects 0.000 claims description 2
- 238000006703 hydration reaction Methods 0.000 claims description 2
- 150000003949 imides Chemical class 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000000376 reactant Substances 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 208000007536 Thrombosis Diseases 0.000 description 7
- 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
- 238000004440 column chromatography Methods 0.000 description 6
- 230000000694 effects Effects 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
- 150000003839 salts Chemical class 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 108010074860 Factor Xa Proteins 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 239000003146 anticoagulant agent Substances 0.000 description 4
- 229940127219 anticoagulant drug Drugs 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- -1 stirring Substances 0.000 description 4
- 238000000967 suction filtration Methods 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
- 210000004351 coronary vessel Anatomy 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 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 description 2
- 208000005189 Embolism Diseases 0.000 description 2
- 208000010378 Pulmonary Embolism Diseases 0.000 description 2
- 208000001435 Thromboembolism Diseases 0.000 description 2
- 208000007814 Unstable Angina Diseases 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 206010000891 acute myocardial infarction Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 125000005909 ethyl alcohol group Chemical group 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 230000001732 thrombotic effect Effects 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- 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
- CPLUGKCOXAPMON-UHFFFAOYSA-N CCOC(CCN(C(c1ccccc11)=O)C1=O)=O Chemical compound CCOC(CCN(C(c1ccccc11)=O)C1=O)=O CPLUGKCOXAPMON-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
- 241000196324 Embryophyta Species 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 206010022562 Intermittent claudication Diseases 0.000 description 1
- OTBOUDMZPFTBMQ-UHFFFAOYSA-N NNC(CCN(C(c1ccccc11)=O)C1=O)=O Chemical compound NNC(CCN(C(c1ccccc11)=O)C1=O)=O OTBOUDMZPFTBMQ-UHFFFAOYSA-N 0.000 description 1
- 0 O=C(CCN(C(c1ccccc11)=O)C1=O)NNS(*(cc1)cc2c1cccc2)(=O)=O Chemical compound O=C(CCN(C(c1ccccc11)=O)C1=O)NNS(*(cc1)cc2c1cccc2)(=O)=O 0.000 description 1
- 235000019082 Osmanthus Nutrition 0.000 description 1
- 241000333181 Osmanthus Species 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 206010043540 Thromboangiitis obliterans Diseases 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
- 238000002583 angiography Methods 0.000 description 1
- 229960005348 antithrombin iii Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 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
- 239000000701 coagulant Substances 0.000 description 1
- 230000006866 deterioration Effects 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
- 229950003499 fibrin Drugs 0.000 description 1
- 230000001939 inductive effect Effects 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
- 210000000936 intestine Anatomy 0.000 description 1
- 201000010849 intracranial embolism Diseases 0.000 description 1
- 210000003127 knee 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
- 210000002381 plasma Anatomy 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002035 prolonged effect 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
- 210000002784 stomach Anatomy 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 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 present invention relates to the drug field related to Venous Thrombosis.Specifically, the present invention relates to FXa inhibitor of the class containing bishydrazide and naphthyl structure, its preparation method and the application in Venous Thrombosis medicine is prepared.Wherein, R is selected from C1‑C3Alkyl.
Description
Technical field
The present invention relates to the drug field of Venous Thrombosis treatment.More particularly, it relates to venous blood
FXa inhibitor, its preparation method of the medicative class of bolt disease containing bishydrazide and naphthyl structure, and in pharmacy
Purposes.
Background technology
The deterioration of clotting ability be unstable angina pectoris, brain osmanthus plug, cerebral embolism, cardiac muscle carry plug, lung infraction, pulmonary embolism,
Buerger's disease, Deep vain thrombosis, disseminated intravascular coagulation, change valve after thrombosis,
Thrombotic key factor during inaccessible again or extracorporal circulatory system after revascularization.In arterial system, abnormal thrombus form master
Relevant with coronary artery, the cerebrovascular and peripheral vascular, the disease relevant with the thrombosis closure of these blood vessels mainly includes
In acute myocardial infarction (AMI), unstable angina, thromboembolism and thromboembolism treatment and percutaneous coronary artery angiography chamber into
The relevant acute vascular closure of shape art (PTCA), transient ischemic attack, apoplexy, Charcot's syndrome and coronary artery bypass are moved
Plant art (CABG) or peripheral arterial BPG.For vein blood vessel, pathologic thrombus are formed often to be occurred in belly, knee
Veins of lower extremity (Deep vain thrombosis, DVT) behind joint and Hip operation.DVT also make patient be in be susceptible to suffer from pulmonary thromboembolism
Highly dangerous among.It is therefore desirable to develop excellent anticoagulant, this anticoagulant have excellent dose response,
Duration is long, bleeding dangerous small, is almost free from side effects, and is to use orally can also quickly reach abundant effect.
According to the research of the mechanism of action to various anticoagulants, coagulation factor xa inhibitors (FXa inhibitor) are considered as
It is good anticoagulant.Factor Xa is second from the bottom kind of enzyme in blood coagulation chain.The inhibitory action of factor Xa passes through
Directly complex is formed between the inhibitor and enzyme and obtain, therefore the enzyme is unrelated with blood plasma confactor Antithrombin III.Have
The factor Xa inhibitory action of effect is administered orally, continuous venoclysis, bolus injection intravenously administrable or any other is non-
Intestines and stomach approach is realized using the compound, thus can obtain and prevent factor Xa from inducing factor formation fibrin ferment
Required effect.Another advantage of FXa inhibitor be effective dose in thrombotic model with experimental Hemorrhage Model in
Prolonging prolonged dosage has very big difference.By this result of the test, it is believed that FXa inhibitor is less anti-hemorrhage risk
Coagulant.Various compounds as FXa inhibitor are had reported, and there is many clinically to ratify, such as razaxaban.
The invention discloses the novel FXa inhibitor containing bishydrazide and naphthyl structure of a class formation, these compounds can
Medicine for preparing treatment Venous Thrombosis.
The content of the invention
It is an object of the present invention to provide a kind of FXa inhibitor of the excellent activity with formula I.
It is a further object to provide method of the preparation with compounds of formula I.
It is also another object of the present invention to provide containing compounds of formula I phlebothrombosis is being treated as active ingredient
Application in terms of disease.
Present invention is specifically described in conjunction with the purpose of the present invention.
The present invention has following structural formula with compounds of formula I：
Wherein, R is selected from H, C1-C4Alkyl, C3-C8Cycloalkyl.
The compound of preferred formula (I) has following structure,
Logical formula (I) compound of the present invention is synthesized by following route：
Compound II first obtains its corresponding acid imide sylvite with KOH reactions, and the latter to ethyl acrylate addition, obtains again
Compound III；Compound III obtains IV with hydration hydrazine reaction；Compound IV reacts with sulfonic acid chloride V in the presence of a base, is changed
Compound I；Wherein, R is defined as described above.
Compound of Formula I of the present invention has the inhibitory action of FXa, can be used to prepare phlebothrombosis as active ingredient
Property medicine.The activity of compound of Formula I of the present invention is verified by receptor binding assays.
Compound of Formula I of the invention is effective in comparatively wide dosage range.The dosage for example taken daily is about
In the range of 1mg-1000mg/ people, it is divided into and once or is for several times administered.The dosage for actually taking compound of Formula I of the present invention can be by
Doctor determines according to relevant situation.
Specific embodiment
With reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments are only for
Illustrate, and be not intended to limit the present invention.The various change that those skilled in the art's training centre of the invention is made all should
Within the protection domain required by the application claim.
The synthesis of the compound I-1 of embodiment 1
A. the synthesis of compound III-1
Compound II-1 (1.92g, 10mmol) is dissolved in 10mL DMSO, is stirred at room temperature, is slowly added into solid KOH
(0.67g, 12mmol), continues to stir 10min, is subsequently adding ethyl acrylate (1.20g, 12mmol), and reactant mixture is then
30min is stirred at room temperature, TLC display reactions are completed.Reactant mixture is poured into 150mL frozen water, stirring, CH2Cl2(50mL
× 3) extract, merge extraction phase, use salt water washing, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is in Rotary Evaporators
On be evaporated, the residue for obtaining is purified using column chromatography, obtains compound III-1, white solid, ESI-MS, m/z=293 ([M
+H]+)。
B. the synthesis of compound IV-1
Compound III-1 (1.46g, 5mmol) is dissolved in 10mL absolute ethyl alcohols, is stirred at room temperature, adds 80% hydrazine hydrate
(0.38g, 6mmol), reactant mixture is then stirred at room temperature 30min, and TLC display reactions are completed.Reactant mixture is toppled over
Enter in 100mL frozen water, stir, CH2Cl2(50mL × 3) extract, and merge extraction phase, use salt water washing, anhydrous sodium sulfate drying.Take out
Drier is filtered, filtrate is evaporated on a rotary evaporator, the residue for obtaining is purified using column chromatography, obtain compound IV-
1, white solid, ESI-MS, m/z=279 ([M+H]+)。
C. the synthesis of compound I-1
Compound IV-1 (0.56g, 2mmol) and triethylamine (0.61g, 6mmol) are dissolved in the dry CH of 5mL2Cl2In, frozen water
The lower stirring of bath cooling, is slowly added dropwise by compound V-1 (0.48g, 2mmol) and the dry CH of 2mL2Cl2The solution of preparation, is added dropwise
Finish rear reactant mixture and 1h is then stirred at room temperature, TLC display reactions are completed.Reactant mixture pours into 100mL frozen water
In, stirring, CH2Cl2(50mL × 3) extract, and merge extraction phase, and successively with 1% watery hydrochloric acid and salt water washing, anhydrous sodium sulfate is done
It is dry.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and the residue for obtaining is purified using column chromatography, obtains chemical combination
Thing I-1, white solid, ESI-MS, m/z=483 ([M+H]+)。
Embodiment 2-3
With reference to the method for embodiment 1, compound listed in Table is synthesized.
The synthesis of the reference compound D-1 of embodiment 4
Compound D-1 is all the compound (not yet being disclosed by the applying date) that the present inventor designs in research process.
A. the synthesis of compound III-4
Compound II-4 (1.47g, 10mmol) is dissolved in 10mL DMSO, is stirred at room temperature, is slowly added into solid KOH
(0.67g, 12mmol), continues to stir 10min, is subsequently adding ethyl acrylate (1.20g, 12mmol), and reactant mixture is then
30min is stirred at room temperature, TLC display reactions are completed.Reactant mixture is poured into 150mL frozen water, stirring, CH2Cl2(50mL
× 3) extract, merge extraction phase, use salt water washing, anhydrous sodium sulfate drying.Suction filtration removes drier, and filtrate is in Rotary Evaporators
On be evaporated, the residue for obtaining is purified using column chromatography, 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 absolute ethyl alcohols, is stirred at room temperature, adds 80% hydrazine hydrate
(0.38g, 6mmol), reactant mixture is then stirred at room temperature 30min, and TLC display reactions are completed.Reactant mixture is toppled over
Enter in 100mL frozen water, stir, CH2Cl2(50mL × 3) extract, and merge extraction phase, use salt water washing, anhydrous sodium sulfate drying.Take out
Drier is filtered, filtrate is evaporated on a rotary evaporator, the residue for obtaining is purified using column chromatography, obtain 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 dry CH of 5mL2Cl2In, frozen water
The lower stirring of bath cooling, is slowly added dropwise by compound V-1 (0.45g, 2mmol) and the dry CH of 2mL2Cl2The solution of preparation, is added dropwise
Finish rear reactant mixture and 1h is then stirred at room temperature, TLC display reactions are completed.Reactant mixture pours into 100mL frozen water
In, stirring, CH2Cl2(50mL × 3) extract, and merge extraction phase, and successively with 1% watery hydrochloric acid and salt water washing, anhydrous sodium sulfate is done
It is dry.Suction filtration removes drier, and filtrate is evaporated on a rotary evaporator, and the residue for obtaining is purified using column chromatography, obtains chemical combination
Thing D-1, white solid, ESI-MS, m/z=424 ([M+H]+)。
Suppression of the Compound ira vitro of embodiment 5 to FXa is tested
By the 5%DMSO solution (10 μ L) of embodiment compound and positive drug EDOXABAN to be measured, (its concentration is progressively
Appropriate setting), Tris buffer solutions (100mM Tris, 200mM potassium chloride, 0.2%BSA, pH 7.4) (40 μ l) and 0.0625U/
(Enzyme Research Labolatories, Inc. with Tris buffer solutions and dilute (10 μ l) and put respectively mL people FXa
Enter in the hole of 96 hole minitype plates, 750 μM of aqueous solution (40 μ l) of S2222 (Chromogenix Co.) are added, to determine 10 minutes
At room temperature in the absorbance of 405nm, so that mensuration absorbance increases (Δ OD/min).As negative control, Tris buffer solutions are used
Instead of test compound.
According to formula below, percent inhibition during by test compound initial concentration and test compound final concentration
(%) is painted on the ordinate and abscissa of the orthogonal probability tables of logarithm respectively, to determine 50% suppression dosage (IC50Value).
Percent inhibition (%)=[1- (the Δ OD/min of sample)/(control Δ OD/min)] × 100
Test result see the table below.
| Compound | |
| Reference compound D-1 (embodiment 4) | 6.7 |
| Compound I-1 | 3.1 |
| Compound I-2 | 3.9 |
| Compound I-3 | 5.8 |
Can be seen that compound of the invention from upper table result is good FXa inhibitor, can be quiet as treatment is prepared
The medicine of arteries and veins thrombotic diseases.
Claims (4)
1. there is the compound of general formula I,
Wherein, R is selected from C1-C3Alkyl.
2. compound of Formula I defined in claim 1, is selected from：
3. the method for synthesizing any defined compounds of formula I of claim 1-2：
Compound II first obtains its corresponding acid imide sylvite with KOH reactions, and the latter to ethyl acrylate addition, obtains chemical combination again
Thing III；Compound III obtains IV with hydration hydrazine reaction；Compound IV reacts with sulfonic acid chloride V in the presence of a base, obtains compound
I；Wherein, the definition of R is as described in claim 1-2 is any.
4. the defined compound of Formula I of one of claim 1-2 prepare treatment Venous Thrombosis medicine in terms of should
With.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710034113.7A CN106800524A (en) | 2015-02-13 | 2015-02-13 | Compound, preparation method and its usage of one class containing bishydrazide and naphthyl structure |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710034113.7A CN106800524A (en) | 2015-02-13 | 2015-02-13 | Compound, preparation method and its usage of one class containing bishydrazide and naphthyl structure |
| CN201510079251.8A CN104710341A (en) | 2015-02-13 | 2015-02-13 | A kind of compound containing bishydrazide and naphthyl structure, preparation method and use thereof |
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| CN201710034113.7A Pending CN106800524A (en) | 2015-02-13 | 2015-02-13 | Compound, preparation method and its usage of one class containing bishydrazide and naphthyl structure |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000071509A1 (en) * | 1999-05-24 | 2000-11-30 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
| WO2009086303A2 (en) * | 2007-12-21 | 2009-07-09 | University Of Rochester | Method for altering the lifespan of eukaryotic organisms |
| CN103228643A (en) * | 2010-09-27 | 2013-07-31 | 生物计划公司 | Benzazole derivatives as histamine H4 receptor ligands |
-
2015
- 2015-02-13 CN CN201510079251.8A patent/CN104710341A/en active Pending
- 2015-02-13 CN CN201710034113.7A patent/CN106800524A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000071509A1 (en) * | 1999-05-24 | 2000-11-30 | Cor Therapeutics, Inc. | INHIBITORS OF FACTOR Xa |
| WO2009086303A2 (en) * | 2007-12-21 | 2009-07-09 | University Of Rochester | Method for altering the lifespan of eukaryotic organisms |
| CN103228643A (en) * | 2010-09-27 | 2013-07-31 | 生物计划公司 | Benzazole derivatives as histamine H4 receptor ligands |
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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| CN104710341A (en) | 2015-06-17 |
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