CN101654446B - Anticoagulant compound, composition and application thereof - Google Patents
Anticoagulant compound, composition and application thereof Download PDFInfo
- Publication number
- CN101654446B CN101654446B CN200810041856A CN200810041856A CN101654446B CN 101654446 B CN101654446 B CN 101654446B CN 200810041856 A CN200810041856 A CN 200810041856A CN 200810041856 A CN200810041856 A CN 200810041856A CN 101654446 B CN101654446 B CN 101654446B
- Authority
- CN
- China
- Prior art keywords
- unsubstituted
- replacement
- compound
- group
- alkyl
- 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
- 0 CC(*)C(C(*c1ccccc11)=O)C1=O Chemical compound CC(*)C(C(*c1ccccc11)=O)C1=O 0.000 description 3
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a compound represented by a formula I or pharmaceutically acceptable salt thereof, a composition comprising the compound or the pharmaceutically acceptable salt thereof, and application of the compound or the pharmaceutically acceptable salt thereof and the composition in anti-coagulation medicaments.
Description
Technical field
The present invention relates to a kind of anticoagulant compound, be specifically related to a kind of new coumarins verivate.
Background technology
The obstacle of coagulation function can cause the disease of serious harm HUMAN HEALTHs such as apoplexy, myocardial infarction and peripheral occlusive arterial disease.Although there are medicines such as heparin and oral tonka bean camphor to can be used for anticoagulation at present, the toxic side effect that these medicines self exist is the problem of clinical doctor's headache always.Along with the continuous propelling of medical fundamental research, people go deep into the understanding of plurality of enzymes, active factor and the associated receptor of participation coagulation process gradually.
Below be several kinds of common drugs that are used for blood coagulation resisting function.
Thrombin inhibitors.Zymoplasm is a Tryase, and it is the key enzyme in the coagulation cascade reaction.Zymoplasm can change the Fibrinogen of solubility into insoluble scleroproein, also can activate factor V, VIII, XI and XII.Vein all is the zymoplasm indirect inhibitor of using always with heparin and oral tonka bean camphor.Along with understanding, some and the direct suppressor factor of zymoplasm specificity bonded have been developed successively to the zymoplasm three-dimensional structure.RWJ-27755, argatroban, Hirugen, Aptamers, r-hirudin and the r-hirudin polypeptide of deriving all is that the direct suppressor factor of zymoplasm can combine with catalytic site.The major advantage of these medicines is can suppress and sludged blood bonded zymoplasm, but shortcoming is the comparison costliness, and the transformation period is shorter, only is applicable to acute treatment.Argatroban has gone on the market and has been used to treat peripheral occlusive arterial disease and acute myocardial infarction.
Except the activity of direct Trombin inhibiting, the another one approach is an exploitation thrombin receptor blocker.Zymoplasm can activate the broad variety cell through the thrombin receptor of cell surface, like thrombocyte, VSMC etc.Because the thrombin receptor blocker does not influence the Fibrinogen-Fibrin approach, the possibility that therefore when accomplishing specific biological action, causes bleeding is very little.The thrombin receptor blocker of exploitation is divided into 3 types now: polypeptide class blocker, polypeptide stand-in blocker and non-peptide receptoroid blocker.
The Xa factor suppressor factor.Xa factor can 138 zymoplasm molecules of catalysis, so the Xa factor suppressor factor is tempting direction in the anticoagulant exploitation.Develop the direct suppressor factor of Xa factor that direction concentrates on non-peptide class, has Orally active at present.Along with the understanding to the Xa factor crystalline structure, the suppressor factor of some site selectivities is also among exploitation.
Tissue factor inhibitor.Tissue factor (TF) is a member of cytokine superfamily, and it is present on some outer cell surface of vascular system.Behind blood vessel injury, TF can combine the one-step activation zymoplasm of going forward side by side with VII and the VIIa factor high specific high-affinity in the blood.The VIIa factor is a kind of weak Tryase, but is combining its enzymic activity of back can strengthen 1,000,000 times with TF.In case the TF:VIIa mixture forms, can trigger the coagulation cascade reaction through two kinds of approach.Therefore, the activity of inhibition tissue factor also is one of development approach of anticoagulant.Also do not have synthetic TF suppressor factor at present, but on endotheliocyte, found physiological TF pathway inhibitor (TFPI), it can prevent thrombosis.At present develop the TFPI (rTFPI) of recombination, on animal model, demonstrated thrombotic ability in the prophylaxis of acute blood vessel.In addition, different with the direct suppressor factor of zymoplasm, the do not cause bleeding prolongation of time of rTFPI.
Plasminogen activator-1 suppressor factor.The formation of thrombus and removing are regulated through the balance between tPA and the PAI-1.The former mediates the generation of plasmin, and the latter is the cracking scleroproein, is the key factor of revascularization.Under some pathologic conditions, like phlebothrombosis, UA, acute myocardial infarction, the level of PAI-1 all might raise.The direct injection thrombolytic drug possibly cause serious hemorrhage untoward reaction like streptokinase, urokinase and tPA, and it is safer to reach the thrombolysis purpose through inhibition PAI-1.The PAI-1 suppressor factor comprises three types, and one type is the antisense nucleic acid suppressor factor to the PAI-1 gene, and one type is to the proteic antibody of PAI-1, and also having one type is the micromolecular compound that can combine PAI-1.
Platelet membrane gp II b/IIIa receptor antagonist.Gp II b/IIIa acceptor is the Fibrinogen integrin receptor, arginine-glycine-aspartic acid acid (RGD) sequence mediation Fibrinogen of Fibrinogen α chain and the combination of gp II b/IIIa acceptor, and this is the final step of platelet activation reaction.It is first member in this type medicine that the Centocor/ gift comes the platelet membrane II b/IIIa suppressor factor-monoclonal antibody ReoPro (Abciximab) of company.This medicine can effectively reduce the ischemic complication after the percutaneous transluminal coronary angioplasty; Though July calendar year 2001, the GUSTOIV-ACS clinical test results of report showed that Abciximab does not have the curative effect of being envisioned to the UA patient; And Abciximab test also suffers from failure (the Reteplase combined utilization of ReoPro and half-value dose is treated acute myocardial infarction in this test to the GUSTOV of acute myocardial infarction; But the result shows to use separately with full dosage Reteplase and compares that 30 days mortality ratio of combination therapy group obviously do not reduce).But as the new class antiplatelet drug, Abciximab is evident in efficacy on some indication, is the very strong competitor of existing antiplatelet drug.Other gp II b/IIIa receptor antagonist contains and comprises ring seven peptide Eptifibatide and non-peptide class RGD sequence stand-in Tirofibans (Tirofiban).Eptifibatide is that the material of a kind of Barbourin of being called of from a kind of crotalic venom, extracting makes through synthetic, and it can be used for treating the complication of unstable angina pectoris and myocardial infarction (MI) initiation.Tirofiban is by the non-peptide class platelet membrane II b/IIIa receptor antagonist of Merck & Co., Inc.'s exploitation, is used to treat acute myocardial infarction and unstable angina pectoris, and go on the market in the U.S. in May, 1998.Oral platelet membrane II b/IIIa receptor antagonist bioavailability is not ideal enough, and the transformation period is short, and also fast with the speed of dissociating of acceptor.
The ADP receptor antagonist.ADP (ADP) is present in the high density granular in the platelet cell; When thrombocyte generation aggregation, be released; ADP can exert an influence to hematoblastic shape and biological behaviour through the adp receptor on the platelet membrane, thereby further quickens hematoblastic agglomeration process.3 kinds of adp receptors are arranged, i.e. P2Y1, P2Y12 and P2X1 on the platelet membrane.P2Y1 is present in thrombocyte and vascular endothelial cell, and P2Y12 exists only on the platelet membrane, so the P2Y12 antagonist can anticoagulant and do not influence the vascular reaction of ADP mediation.At present, P2Y12 antagonist class medicine has clopidogrel (Clopidogrel), ticlopidine (Ticlopidine) and CS-747.The P2Y1 antagonist also has significant anticoagulant effect, and this compounds comprises A2P5P (2 ', 5 '-ADP) and A3P5P (3 ', 5 '-ADP) and MRS-2197 at present.
Though above-mentioned anticoagulant has certain anti-freezing effect, at present this area also need anti-freezing better effects if, spinoff still less, toxicity is littler, uses is more convenient and the easy medicine of preparation.
Summary of the invention
In order to solve the problems of the technologies described above, contriver of the present invention is through discover in a large number, and some coumarins verivates have extraordinary anti-freezing effect, and its spinoff still less, toxicity is littler, use is more convenient and preparation easily.
The invention provides compound or its pharmacy acceptable salt that a kind of following formula I is represented,
Formula I
In the formula: X and Y are identical or different, are selected from hydrogen, replacement or unsubstituted C1-C10 alkyl, replacement or unsubstituted C6-C10 aryl, replacement or unsubstituted C3-C10 naphthenic base, replacement or unsubstituted heteroaryl, replacement or unsubstituted C2-C10 thiazolinyl, replacement or unsubstituted C1-C10 alkoxyl group or replacement or unsubstituted C2-C10 alkynyl separately;
R is selected from hydrogen, halogen, hydroxyl, replacement or unsubstituted C1-C10 alkyl, replacement or unsubstituted C1-C10 alkoxyl group, replacement or unsubstituted C6-C10 aryl, replacement or unsubstituted C3-C10 naphthenic base and replacement or unsubstituted heteroaryl;
Above-mentioned substituting group can be identical or different, is selected from hydrogen, halogen, hydroxyl, C1-C10 alkyl, C1-C10 alkoxyl group, acyl group, carboxamido-group, aryl and cyanic acid separately.
In a preferred embodiment of the present invention; X and Y are identical or different, are selected from hydrogen, replacement or unsubstituted C1-C6 alkyl, replacement or unsubstituted C6-C9 aryl, replacement or unsubstituted C3-C6 naphthenic base, replacement or unsubstituted five-ring or six-ring heteroaryl, replacement or unsubstituted C2-C6 thiazolinyl, replacement or unsubstituted C1-C6 alkoxyl group or replacement or unsubstituted C2-C6 alkynyl separately;
X and Y preferably are selected from hydrogen, replacement or unsubstituted C1-C4 alkyl, replacement or unsubstituted phenyl, replacement or unsubstituted C3-C5 naphthenic base, replacement or unsubstituted five-ring heteroaryl, replacement or unsubstituted C2-C4 thiazolinyl, replacement or unsubstituted C1-C4 alkoxyl group or replacement or unsubstituted C2-C4 alkynyl separately;
X and Y preferably are selected from hydrogen separately; Replace or unsubstituted methyl; Replace or unsubstituted ethyl; Replace or unsubstituted propyl group; Replace or unsubstituted butyl; Phenyl; The substituted phenyl of alkyl; The substituted phenyl of alkoxyl group; Replace or unsubstituted pentamethylene base; Replace or unsubstituted vinyl; Replace or unsubstituted thienyl; Replace or unsubstituted ethynyl; Replace or unsubstituted methoxyl group; Replace or unsubstituted oxyethyl group; Replace or unsubstituted propoxy-; Replace or unsubstituted butoxy; Replace or unsubstituted furyl and replacement or unsubstituted pyrryl.
In a preferred embodiment of the present invention, R is selected from hydrogen, halogen, hydroxyl, replacement or unsubstituted C1-C6 alkyl, replacement or unsubstituted C1-C6 alkoxyl group, replacement or unsubstituted C6-C8 aryl, replacement or unsubstituted C3-C6 naphthenic base and replacement or unsubstituted five-ring or six-ring heteroaryl;
R is preferably selected from hydrogen; Halogen; Hydroxyl; Replace or unsubstituted methyl; Replace or unsubstituted ethyl; Replace or unsubstituted propyl group; Replace or unsubstituted butyl; Replace or unsubstituted methoxyl group; Replace or unsubstituted oxyethyl group; Replace or unsubstituted propoxy-; Replace or unsubstituted butoxy; Replace or unsubstituted phenyl; Replace or unsubstituted cyclopropyl; Replace or unsubstituted thienyl; Replace or unsubstituted furyl and replacement or unsubstituted pyrryl.
In a preferred embodiment of the present invention, said substituting group is selected from hydrogen, oxygen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyl group, acyl group, carboxamido-group, aryl and cyanic acid;
Said substituting group better is selected from hydrogen, oxygen, halogen, hydroxyl, C1-C4 alkyl, C1-C4 alkoxyl group, acyl group, carboxamido-group, aryl and cyanic acid.
Said substituting group preferably is selected from hydrogen, oxygen, halogen, hydroxyl, methyl, ethyl, propyl group, butyl, methoxyl group, oxyethyl group, propoxy-, butoxy, formyl radical, ethanoyl, propionyl group, butyryl radicals and formamido-.
The present invention also provides a kind of anticoagulant pharmaceutical composition that is used for, and said compsn comprises compound according to the invention or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
In a preferred embodiment of the present invention, pharmaceutical composition is the oral or non-oral dosage form of the form of granula, pulvis, tablet, capsule, syrup, suppository, injection, emulsion, tincture, suspension-s, solution.
Compound according to the invention or its pharmacy acceptable salt purposes in the preparation anticoagulation medicine.
In a preferred embodiment of the present invention, said anticoagulation medicine is used for prevention and treatment thrombotic disease; Prevention and treatment operation back or post-traumatic venous thrombosis; Prevention and treatment myocardial infarction; Prevention thromboembolism patient's complication and postoperative thrombus complication.
The accompanying drawing summary
Fig. 1 is the nucleus magnetic resonance figure of embodiment 1 gained compound.
Fig. 2 is the nucleus magnetic resonance figure of embodiment 2 gained compounds.
Fig. 3 is the nucleus magnetic resonance figure of embodiment 3 gained compounds.
Fig. 4 is the nucleus magnetic resonance figure of embodiment 4 gained compounds.
Fig. 5 is the nucleus magnetic resonance figure of embodiment 5 gained compounds.
Fig. 6 is the nucleus magnetic resonance figure of embodiment 6 gained compounds.
Fig. 7 is the nucleus magnetic resonance figure of embodiment 7 gained compounds.
Fig. 8 is the nucleus magnetic resonance figure of embodiment 8 gained compounds.
Fig. 9 is the nucleus magnetic resonance figure of embodiment 9 gained compounds.
Embodiment
A kind of anticoagulant of present commercial use is a warfarin, but the warfarin overdosage use is prone to cause various hemorrhage.Early stage performance has that ecchymosis, purpura, gingival hemorrhage, nosebleed epistaxis, wound bleeding are not prolongedly healed, excessive menstruation etc.Hemorrhage any position, particularly uropoiesis and the digestive tube of occurring in.Intestines wall hemotoncus can cause subacute intestinal obstruction, intracranial hematoma and site of puncture hemotoncus under the also visible dura mater.Accidental untoward reaction has nausea,vomiting,diarrhea, itch property fash, anaphylaxis and cutaneous necrosis.A large amount of oral warfarins in addition occur that the bilateral breast is downright bad, microangiopathy or hemolytic anemia and gangrene of skin on a large scale; Once measure excessive especially danger.And warfarin is bigger for difference between individuals, answers the tight observation state of an illness during the treatment, and according to prothrombin time INR value adjustment consumption.Also answer tight observation oral mucosa, nasal cavity, subcutaneous hemorrhage and stool blood, blood urine etc. during the treatment; Should avoid unnecessary operation technique during the medication; The person answered drug withdrawal 7 days to select the stage operation, and the emergency operation person need correct PTINR value≤1.6, avoid overworked be prone to cause the activity of damage.If hyporrhea takes place, or prothrombin time significant prolongation should be decrement or drug withdrawal to normal more than 2.5 times.Severe haemorrhage can quiet notes vitamin K l10～20mg, in order to control over bleeding, can fail whole blood, blood plasma or Prothrombin Complex Concent-in case of necessity.
The present invention carries out structural modification according to structure activity relationship on the original chemical basis of warfarin, to improve or to keep the anti-freezing and the platelet aggregation-against function of warfarin reason, reduce toxic side effect simultaneously.The original treatment window of warfarin narrow range, and difference between individuals is bigger.And warfarin verivate (coumarin derivatives) can enlarge treatment window scope, thereby reduces toxic side effect, guarantees the security of medication.
In the present invention, except as otherwise noted, " alkyl " refer to the replacement of C1-C10 or do not replace, the straight or branched alkyl, better be C1-C8, better have C1-C6, preferably C1-C4 replacement or do not replace, the straight or branched alkyl.
In the present invention, except as otherwise noted, " alkoxyl group " refer to the replacement of C1-C10 or do not replace, the straight or branched alkyl, better be C1-C8, be more preferably C1-C6, preferably C1-C4 replacement or do not replace, the straight or branched alkyl.
In the present invention, except as otherwise noted, " halogen " or " halogen " refers to fluorine, chlorine, bromine and/or iodine.
In the present invention, except as otherwise noted, " halo " expression is replaced by one or more halogen atoms, for example a halo, dihalo, perhalogeno (for example perfluor) etc.
In the present invention, except as otherwise noted, " aromatic base " or " aryl " refers to have the replacement of C6-C20 or substituted aromatic group not, better is C6-C16, is more preferably C6-C14, preferably replacement or the unsubstituted aromatic group of C6-C10.Phenyl for example
In the present invention, except as otherwise noted, have one or more heteroatomic aryl in the female ring of " heteroaryl " expression.Said heteroatoms can be oxygen, sulphur and/or nitrogen.
In the present invention, except as otherwise noted, the substituting group of " acyl group " expression following formula :-C (O) R
1, wherein R is an alkyl.
In the present invention, except as otherwise noted, the substituting group of " carboxamido-group " expression following formula :-C (O) NR
2R
3, R wherein
2And R
3Can be identical or different, represent hydrogen, alkyl, alkoxyl group etc. separately, and R
2And R
3Can be combined to form ring.
In the present invention, except as otherwise noted, " substituting group " expression hydrogen, oxygen, halogen, hydroxyl, C1-C10 alkyl, C1-C10 alkoxyl group, acyl group, carboxamido-group, aryl and cyanic acid.
In the present invention, except as otherwise noted, percentage composition and part are all represented weight.
Only if having in addition said, all preferred technique schemes of the present invention can any-mode combination, these technical schemes that combine include in the present invention's scope required for protection.
The invention provides the compound that a kind of following formula I is represented,
Formula I
In the formula: X and Y are identical or different, are selected from hydrogen, replacement or unsubstituted C1-C10 alkyl, replacement or unsubstituted C6-C10 aryl, replacement or unsubstituted C3-C10 naphthenic base, replacement or unsubstituted heteroaryl, replacement or unsubstituted C2-C10 thiazolinyl, replacement or unsubstituted C1-C10 alkoxyl group or replacement or unsubstituted C2-C10 alkynyl separately;
R is selected from hydrogen, halogen, hydroxyl, replacement or unsubstituted C1-C10 alkyl, replacement or unsubstituted C1-C10 alkoxyl group, replacement or unsubstituted C6-C10 aryl, replacement or unsubstituted C3-C10 naphthenic base and replacement or unsubstituted heteroaryl;
Above-mentioned substituting group can be identical or different, is selected from hydrogen, halogen, hydroxyl, C1-C10 alkyl, C1-C10 alkoxyl group, acyl group, carboxamido-group, aryl and cyanic acid separately.
In formula I compound of the present invention; X and Y are identical or different, are selected from hydrogen, replacement or unsubstituted C1-C10 alkyl, replacement or unsubstituted C6-C10 aryl, replacement or unsubstituted C3-C10 naphthenic base, replacement or unsubstituted heteroaryl, replacement or unsubstituted C2-C10 thiazolinyl, replacement or unsubstituted C1-C10 alkoxyl group or replacement or unsubstituted C2-C10 alkynyl separately.
In a preferred examples; X and Y are identical or different, are selected from hydrogen, replacement or unsubstituted C1-C6 alkyl, replacement or unsubstituted C6-C9 aryl, replacement or unsubstituted C3-C6 naphthenic base, replacement or unsubstituted five-ring or six-ring heteroaryl, replacement or unsubstituted C2-C6 thiazolinyl, replacement or unsubstituted C1-C6 alkoxyl group or replacement or unsubstituted C2-C6 alkynyl separately.
In another preferred embodiment of the present invention; X and Y are identical or different, are selected from hydrogen, replacement or unsubstituted C1-C4 alkyl, replacement or unsubstituted phenyl, replacement or unsubstituted C3-C5 naphthenic base, replacement or unsubstituted five-ring heteroaryl, replacement or unsubstituted C2-C4 thiazolinyl, replacement or unsubstituted C1-C4 alkoxyl group or replacement or unsubstituted C2-C4 alkynyl separately.
In another preferred embodiment of the present invention; X and Y are identical or different, are selected from hydrogen, replacement or unsubstituted methyl, replacement or unsubstituted ethyl, replacement or unsubstituted propyl group, replacement or unsubstituted butyl, phenyl, the substituted phenyl of alkyl, the substituted phenyl of alkoxyl group, replacement or unsubstituted pentamethylene base, replacement or unsubstituted vinyl, replacement or unsubstituted thienyl, replacement or unsubstituted ethynyl, replacement or unsubstituted methoxyl group, replacement or unsubstituted oxyethyl group, replacement or unsubstituted propoxy-, replacement or unsubstituted butoxy, replacement or unsubstituted furyl and replacement or unsubstituted pyrryl separately.
In the present invention, R is selected from hydrogen, halogen, hydroxyl, replacement or unsubstituted C1-C10 alkyl, replacement or unsubstituted C1-C10 alkoxyl group, replacement or unsubstituted C6-C10 aryl, replacement or unsubstituted C3-C10 naphthenic base and replacement or unsubstituted heteroaryl.
In a preferred embodiment of the present invention, R is selected from hydrogen, halogen, hydroxyl, replacement or unsubstituted C1-C6 alkyl, replacement or unsubstituted C1-C6 alkoxyl group, replacement or unsubstituted C6-C8 aryl, replacement or unsubstituted C3-C6 naphthenic base and replacement or unsubstituted five-ring or six-ring heteroaryl.
In another preferred embodiment of the present invention, R is selected from hydrogen, halogen, hydroxyl, replacement or unsubstituted C1-C4 alkyl, replacement or unsubstituted C1-C4 alkoxyl group, replacement or unsubstituted phenyl, replacement or unsubstituted cyclopropyl and replacement or unsubstituted five-ring heteroaryl.
In another preferred embodiment of the present invention, R is selected from hydrogen, halogen, hydroxyl, replacement or unsubstituted methyl, replacement or unsubstituted ethyl, replacement or unsubstituted propyl group, replacement or unsubstituted butyl, replacement or unsubstituted methoxyl group, replacement or unsubstituted oxyethyl group, replacement or unsubstituted propoxy-, replacement or unsubstituted butoxy, replacement or unsubstituted phenyl, replacement or unsubstituted cyclopropyl, replacement or unsubstituted thienyl, replacement or unsubstituted furyl and replacement or unsubstituted pyrryl.
In the present invention, above-mentioned substituting group can be identical or different, is selected from hydrogen, oxygen, halogen, hydroxyl, C1-C10 alkyl, C1-C10 alkoxyl group, acyl group, carboxamido-group, aryl and cyanic acid separately.
In a preferred embodiment of the present invention, said substituting group is selected from hydrogen, oxygen, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxyl group, acyl group, carboxamido-group, aryl and cyanic acid.
In another preferred embodiment of the present invention, said substituting group is selected from hydrogen, oxygen, halogen, hydroxyl, C1-C4 alkyl, C1-C4 alkoxyl group, acyl group, carboxamido-group, aryl and cyanic acid.
In another preferred embodiment of the present invention, said substituting group is selected from hydrogen, oxygen, halogen, hydroxyl, methyl, ethyl, propyl group, butyl, methoxyl group, oxyethyl group, propoxy-, butoxy, formyl radical, ethanoyl, propionyl group, butyryl radicals and formamido-.
In a preferred embodiment of the present invention, said formula I compound is selected from the compound that following formula is represented:
Compound of the present invention also comprises enol isomer or its pharmacy acceptable salt, for example sodium salt, the sylvite etc. of above-claimed cpd.Can think that enol isomer or its pharmacy acceptable salt of compound according to the invention also have identical technique effect.
The present invention provides above-claimed cpd to treat and prevent purposes in the following medicine in preparation on the other hand: prevention and treatment thrombotic disease; Prevention and treatment operation back or post-traumatic venous thrombosis; Prevention and treatment myocardial infarction; Prevention thromboembolism patient's complication and postoperative thrombus complication.
Compound effects mechanism of the present invention is competitive effect to antivitamin K, and thrombin is synthetic in the inhibition liver cell, also has the effect of the platelet aggregation reaction that reduces thrombin induction, thereby has anti-freezing and platelet aggregation-against function.
The present invention also provides the pharmaceutical composition that comprises above-claimed cpd, and said pharmaceutical composition comprises the pharmaceutically acceptable carrier of compound shown in the formula I that treats significant quantity and treatment significant quantity.
Pharmaceutical composition of the present invention can be processed pharmaceutical dosage form commonly used through ordinary method.Pharmaceutical dosage form commonly used comprises the oral or non-oral administration of form of granula, pulvis, tablet, capsule, syrup, suppository, injection, emulsion, tincture, suspension-s, solution.
For oral administration, can use tablet, lozenge, capsule, pill, powder, particle, paste, suspensoid, emulsion or solution.
For parenteral administration, can use injection and infusion solution.
For intra-articular injection, can use the suspensoid of corresponding configuration.
For intramuscular injection, can use the aqueous solution and oil solution or suspensoid and corresponding depots preparation.
For external local application, can use lotion, creme and gelifying agent etc.
Active compound of the present invention can be mixed with oral administration, the cheek administration, and intranasal administration, parenterai administration (for example intravenous injection, intramuscular or subcutaneous administration) or rectal administration form perhaps are mixed with the suitable form of medication that sucks or be blown into.The preparation of the sustained-release administration that activeconstituents of the present invention can also be processed.
For oral administration, pharmaceutical composition for example can adopt tablet or capsular form, uses pharmaceutically acceptable vehicle through the ordinary method preparation.Vehicle for example has tamanori (for example the W-Gum of pre-gelledization, polyvinylpyrrolidine base ketone or HYDROXY PROPYL METHYLCELLULOSE); Weighting agent (for example lactose, Microcrystalline Cellulose or calcium phosphate); Lubricant (for example talcum powder or silicon oxide); Disintegrating agent (for example W-Gum or sodium starch glycolate); Or wetting agent (for example sodium lauryl sulphate).Tablet can use method dressing well known in the art.The liquid preparation of oral administration for example can be a solution, syrup or suspension-s, and perhaps they can be the products of doing, water or other appropriate excipients are processed liquid preparation before using.This liquid preparation can use pharmaceutically acceptable additive to use conventional method preparation, said additive such as suspension agent (for example sorbitol syrups, methylcellulose gum or hydrogenation edible-fat); Emulsifying agent (for example Yelkin TTS or gum arabic); Non-water vehicle (for example Prunus amygdalus oil, buttery ester or alcohol); And sanitas (for example methyl or propyl para-hydroxybenzoate or Sorbic Acid).
For the cheek administration, compsn can be the tablet or the lozenge of ordinary method preparation.
Active compound of the present invention can be processed the non-intestinal drug delivery agent of injection, comprises using conventional insertion conduit or inculcating the preparation of method administration.Injection formulations exists with unit form, and for example ampere or multi-dose container wherein add sanitas.This compsn can be the suspension-s in oil or water vehicle, the form of solution or emulsion, and can contain preparaton such as suspension agent, stablizer and/or dispersion agent.Activeconstituents can be a powder type in addition, is mixed with liquid preparation with suitable vehicle such as aseptic apyrogenic water before using.
Active compound of the present invention can also be mixed with the compsn of rectal administration, and for example the enema of suppository or delay for example contains the conventional suppository base such as the enema of theobroma oil or glyceryl ester.
The effective dose of used activeconstituents can change with the severity of the pattern of administration and disease to be treated.Yet, when compound of the present invention every day gives with the dosage of about 0.3-30mg/kg the weight of animals, can obtain gratifying effect usually, preferably give with the dosage that separates for 2-4 time every day, or with the slowly-releasing form administration.As far as most of large mammal, the total dose of every day is about 1-30mg.Be applicable to dosage form for oral administration, comprise active compound with the about 0.3-30mg of solid-state or liquid pharmaceutically acceptable carrier blended.This dosage of adjustable is replied so that optimal treatment to be provided.For example, by an urgent demand of treatment situation, but give the dosage that several times separate every day, or dosage is reduced pari passu.Usually, the range of choice of the suitable clinical dosage of adult oral every day is 1-1000mg, is preferably 10-200mg, and non-oral dosage every day of being grown up is 0.1-100mg, preferred 1-30mg.
In an embodiment of the present invention, agents useful for same is following:
Embodiment
Embodiment 1: the preparation of formula 4 compounds
Put into the 150ml there-necked flask to 30.3g (0.3mol) triethylamine.Under normal temperature, water-bath, stirring, splash into 34.5g (0.75mol) formic acid.Drip off the bath of anhydrating of dropping back, add 6.48g (40mmol) tonka bean camphor (formula 1) and 5.28g (40mmol) phenylacrolein (formula 2).On flask, load onto the argon gas ball, be placed on flask in 140-150 ℃ the oil bath and stirred 2 hours.Cooling is poured reaction solution in the 300ml water into then, and product becomes the thickness glue to separate out.The layer that anhydrates that inclines then with the 150ml washing once, is adding 100ml ethanol.Heating makes the crude product dissolving near boiling, rocks down then slowly to add 20ml water, places 1 hour, separates out mass crystallization.Filter, then wash, descended dry 10 hours in ir lamp then with 10ml ethanol.Took out 10 hours in 70 ℃ with oil pump again, obtain the 5.5g product, productive rate 49.5%.
Above product 5.0g is suspended in the 20ml methyl alcohol, adds the solution of 0.75gNaOH (1.0 equivalent) in 10ml methyl alcohol, heating a little makes it dissolving.Boil off methyl alcohol and obtain oily matter, add 30ml ETHYLE ACETATE then,, separate out solid very soon with glass stick friction bottle wall or adding crystal seed.Suction filtration, then with ETHYLE ACETATE wash solid.Earlier take out most of solvent, took out 3 hours in 50 ℃ with oil pump again with surge pump, must the 5.4g white powder.
Embodiment 2: the preparation of formula 8 compounds
(3.66g 30mmol) is dissolved in the 120ml acetone, adds 8.7g (75mmol) salt of wormwood and 3.7ml (60mmol) methyl iodide salicylic aldehyde.Argon shield refluxed 2 hours.Remove by filter salt of wormwood then, evaporate to dryness.Add 30ml ETHYLE ACETATE again, filter once then, evaporate to dryness obtains the crude product of formula 6.
Put into the 100ml there-necked flask to 20.2g (0.2mol) triethylamine, splash into 23.0g (0.50mol) formic acid under the normal temperature stirring in water bath, drip off the bath of anhydrating of dropping back, add 4.33g (27mmol) tonka bean camphor and the above formula that obtains 6 compounds.On flask, load onto the argon gas ball, be placed on flask in the 140-150 ℃ of oil bath and stirred 2 hours.Cooling is poured reaction solution in the 200ml water into then, and product becomes the thickness glue to separate out.The layer that anhydrates that inclines, with the 100ml washing once, the gained jelly dissolves with methylene dichloride again, again with the aqueous sodium hydroxide solution 60ml extraction of 1N.Discard organic layer, water layer is used ethyl acetate extraction twice then with the hydrochloric acid 40ml acidifying of 2N, merges organic layer.Use the anhydrous sodium sulfate drying organic layer, drain foam.With about 40ml ETHYLE ACETATE heating for dissolving, add sherwood oil then product is become turbid at 50 ℃, be placed on again in 50 ℃ of oil baths and add crystal seed, make oil bath in 5-6 hour, slowly drop to room temperature.Put 10 hours in room temperature then, obtain oarse-grained rib shape crystal 3 .0g, productive rate is 40%.
Above crystal 990mg is dissolved in methyl alcohol, adds the solution of 146mg NaOH (1.0 equivalent) in methyl alcohol again, heating a little makes it dissolving.Boil off methyl alcohol, add 10ml methyl alcohol again, drain, three times to remove moisture repeatedly.Under 70 ℃ of water-baths, took out two hours at last, form the about 1.05g of pulverulent solids, obtain formula 8 compounds with surge pump.
In reaction flask, add 2ml compound (3-1), use the 20ml dissolve with ethanol, stir adding 1.3ml compound (3-2) down.Drip 10%KOH 1.12 grams, stirring at room is separated out a large amount of solids.Continue to stir 1 hour, filter.Filter cake is with the washing in 20: 1 of sherwood oil-ethanol, and drying under reduced pressure, gets compound (3-3) 1.64 grams, yield 51.5%.
In the 2.5ml pyridine, add 0.81g compound (3-4), stir entirely and dissolve.Add 0.77g compound (3-3) again, dissolve entirely in room temperature.0.5 have solid to separate out after hour, separate out a large amount of solids behind the adding 10ml water.Filter filter cake water and ether washing, dry 1.38g compound (3-5), the yield 91.4% of getting.
The 30ml glacial acetic acid and with the 5ml concentrated hydrochloric acid in add 6.32g compound (3-5).Be heated to backflow, stirred 3 hours, be cooled to room temperature then, pour in the frozen water, stir.Filter, filter cake adds the 10%KOH alkalization, and the full back of dissolving is with extracted with diethyl ether 3 times.Discard organic layer, water layer stirred 48 hours to pH=2 with the 1N hcl acidifying.Filter, filter cake is used water washing, and drying under reduced pressure gets 3.787g compound (3-6), yield 68%.
In reaction flask, add 310mg compound (3-6), 834ml, 5ml benzene is heated to backflow, solvent is steamed cooling.Be heated to 170 ℃ of reactions.Use the acetic acid ethyl dissolution reaction solution, use water washing, use anhydrous sodium sulfate drying then.Filter, filtrate decompression concentrates, and uses column chromatography then, and chromatographic solution is a sherwood oil: ETHYLE ACETATE 2.5: 1.Concentrate chromatographic solution, get white crystal 107mg compound (3-7), yield 32%.
In reaction flask, add 2ml compound (4-1), use the 20ml dissolve with ethanol, stir adding 1.3ml compound (4-2) down.Drip 10%KOH 1.12 grams, stirring at room is separated out a large amount of solids.Continue to stir 1 hour, filter.Filter cake is with the washing in 20: 1 of sherwood oil-ethanol, and drying under reduced pressure gets compound (4-3) 1.64 grams, yield 51.5%.
In the 2.5ml pyridine, add 0.81g compound (4-4), stir entirely and dissolve.Add 0.77g compound (4-3) again, dissolve entirely in room temperature.0.5 there is solid to separate out after hour, add 10ml water, separate out a large amount of solids.Filter filter cake water and ether washing, dry 1.38g compound (4-5), the yield 91.4% of getting.
The 30ml glacial acetic acid and with the 5ml concentrated hydrochloric acid in add 6.32g compound (4-5).Be heated to backflow, stirred 3 hours, be cooled to room temperature then, pour in the frozen water, stir.Filter, filter cake is with adding the 10%KOH alkalization, and the full back of dissolving is with extracted with diethyl ether 3 times.Discard organic layer, water layer, stirred 48 hours to pH=2 with the 1N hcl acidifying.Filter, filter cake is used water washing, and drying under reduced pressure gets 3.787g compound (4-6), yield 68%.
In reaction flask, add 310mg compound (4-6); 1ml
is heated to 170 ℃; Reacted cooling 1.5 hours.Use the acetic acid ethyl dissolution reaction solution, use water washing, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and uses column chromatography the chromatographic solution sherwood oil: ETHYLE ACETATE 2.5: 1.Chromatographic solution concentrates, and gets white solid 156mg, yield 41%.Use the toluene recrystallization, get white solid 76mg compound (4-7).
Embodiment 5
Synthesizing of compound 1
With 25mL N, dinethylformamide adds in the 100mL flask, under ice bath, is cooled to 0 ℃; Slowly drip the 15mL POCl3, remove ice bath and return to the thiophene that adds 4.2g behind the stirring at room 0.5h, slowly be warming up to 80 ℃ of following stirring reaction 3h postcooling to room temperature; Reaction solution is slowly added in the 100g trash ice, regulate pH value to 6 with 10% sodium hydroxide after, with ethyl acetate extraction three times; Wash three times, saturated sodium-chloride water solution washs once, through the dried over sodium sulfate after-filtration; Evaporate to dryness obtains 3.606g sorrel fluid cpds 1, productive rate 64%.
The Synthetic 2 of compound
1.90g compound 1 and 4.92g acetone are mixed in (compound 1 is insoluble) in the 80mL water, and solution becomes green at once behind the adding 362mg tetramethyleneimine, and compound 1 russet disappears very soon, stirs stopped reaction after 15 hours.Reaction solution with three after washings of dichloromethane extraction once; The saturated sodium-chloride water solution washing once; Dried over sodium sulfate after-filtration evaporate to dryness; (sherwood oil: ETHYLE ACETATE=10: 1) separate, obtain the slightly assorted compound 2 of 455mg pure compound 2 and 1.177g, impurity wherein mainly is the intact raw material of unreacted to column chromatography.。
Synthesizing of compound 4
Embodiment 6
Synthesizing of compound 6
6.36g phenyl aldehyde and 3.96g propane dinitrile are dissolved in the 60mL ethanol; 10% of adding 3.36g potassium hydroxide aqueous solution after stirring; Behind the stirring at room reaction 0.5h, filter out solid sediment, wash three times with the mixing solutions of sherwood oil and ethanol (20: 1) after; Vacuum-drying obtains 5.96g compound 6, productive rate 65%.
Synthesizing of compound 7
6.2g compound 3 (4 hydroxy coumarin) is dissolved in the 30ml pyridine, adds 5.9g compound 6, adding distil water 50mL behind the reaction 1h under the room temperature; Filter out solid sediment; Use the ether washed twice behind the water thorough washing again, vacuum-drying gets the compound 7 of 11.15g, productive rate 92%.
Synthesizing of compound 8
Synthesizing of compound 10
Synthesizing of compound 11
143mg compound 8 (seeing the midbody of preparation SAR12) is dissolved in the 5mL methylene dichloride, adds the 49mg triethylamine, all dropwise add the 50mg Vinyl chloroformate after the dissolving; Feed ammonia behind the stirring reaction 2h under the room temperature, behind the stirring at room reaction 12h, add 30mL zero(ppm) water; Equal 1 back with ethyl acetate extraction three times with 2N hcl acidifying to pH value, wash twice, saturated sodium-chloride water solution washs once; After the dried over sodium sulfate, filter evaporate to dryness and obtain 30mg compound 11.
Synthesizing of compound 12
62mg compound 11 and 35mg p-methyl benzene sulfonic chloride are dissolved in the 6ml methylene dichloride, add the 73mg triethylamine, react 12h under the stirring at room; Add the 20mL methylene dichloride; Wash secondary with saturated aqueous sodium carbonate, saturated sodium-chloride water solution washs once, dried over sodium sulfate; Obtain 68mg compound 12, productive rate 80% after filtering evaporate to dryness.The Triethylammonium chloride of noting this step must wash clean, otherwise the reaction of back can't obtain title product.
Synthesizing of compound 13
65mg compound 12 is dissolved in the 3mL acetonitrile, adds 0.1mL formic acid and 20mg Paraformaldehyde 96 again, at the protection refluxed reaction 11h of argon gas.In reaction solution, add 20mL zero(ppm) water, use ethyl acetate extraction, wash secondary afterwards, saturated sodium-chloride water solution washs once, after the dried over mgso, filters evaporate to dryness, column chromatography (sherwood oil: ETHYLE ACETATE=3: 1) get 40mg compound 13.
Synthesizing of compound 14
260mg compound 13 is dissolved in the 10mL anhydrous tetrahydro furan, adds the tetrabutyl ammonium fluoride solution (tetrahydrofuran solution of 1mol/L) of 2.4mL, add 20mL zero(ppm) water under the room temperature behind the stirring reaction 0.5h; Behind ethyl acetate extraction; Wash once, saturated nacl aqueous solution washs once, dried over sodium sulfate; Filter evaporate to dryness; Column chromatography (sherwood oil: ETHYLE ACETATE=1: 1,5 acetate/300mL elutriants) is got the compound 14 of 81mg, with obtaining the pure compound of 59mg 14 behind the methylene dichloride recrystallization.
Tonka bean camphor (industrial goods, chemical industry ltd is thought to reach by Jintan City)
Monobromethane YLENE (95%, import, Shenzhen Mai Ruier company)
Sodium methylate (CP level, Shanghai Ling Feng chemical reagent ltd)
Put into the 250ml there-necked flask to the 80ml THF, drop into 4.05 gram tonka bean camphors and 2.70 gram sodium methylates.Heated and stirred.Be heated to backflow.7.40 gram monobromethane xylene soluble in the 80ml THF, are dropwise added reaction solution.Added the back back flow reaction 4 hours.Stopped reaction, cooling.Filtration, filtrate decompression concentrates, and adds proper amount of acetone, and crystallizing at room temperature is filtered, and gets the white granular crystal, and vacuum-drying gets product 2.5 grams, yield 30.4%.
Embodiment 9
Put into 250ml there-necked flask (mouth adds drying tube, and a mouth adds tap funnel) to the NaH of 4.0 gram (100mmol) 60%, adding the 80ml THF.Put into the normal temperature water-bath to flask, stir and slowly splash into the solution (control rate of addition do not want reaction too fierce) of 16.0g (100mmol) ethyl malonate (1) in the 20ml THF down, drip off the back and stirred ten minutes.Slowly splash into the solution of 17.9g (120mmol) bromo isopentene (2) in the 20ml THF, have a large amount of white precipitates to occur.Drip the back stirring at room 30 minutes, add 80ml water then, transfer in the 500ml single port flask and take out THF, residuum extracts with ETHYLE ACETATE 50ml*3.Merge organic layer, wash, use dried over sodium sulfate then with saturated NaCl.Revolve to steam to remove and desolvate, get crude product.With the dissolving of a small amount of methylene dichloride, upper prop use sherwood oil: ETHYLE ACETATE=35: 1 wash-outs, concentrated 11g, yield 48.2%.
Dry used instrument, logical argon shield.In two mouthfuls of bottles of 50ml, add 3.6g (20mmol) acetoxybenzoic acid, 0.1g urea, be suspended in the 20ml toluene, inject 1.75ml (24mmol) sulfur oxychloride then, reflux.Stirred 1 hour, this moment, reaction solution was yellow clarification, was cooled to room temperature then.
Dry used instrument, logical argon shield.The sodium hydride and the 30ml THF that in the 150ml there-necked flask, add 0.96g (24mmol) 60% stir and inject 5.5g (24mmol) compound 3 solution at the 10ml THF down, and reaction solution becomes clearly gradually.Inject to go up the step reaction solution after 15 minutes, in stirring at room 3 hours, the some plate.Add 50ml water termination reaction then, use ethyl acetate extraction last time, merge organic layer.Use saturated sodium bicarbonate, water, saturated common salt water washing successively, use anhydrous sodium sulfate drying.Filter, filtrate decompression concentrate crude product.Crude product is used a small amount of dichloromethane solvent, and upper prop is used sherwood oil: ETHYLE ACETATE=8: 1 wash-outs, concentrate 4.15g, yield 53%.
1.87g (4.8mmol) compound (6) is dissolved in the 33ml ethanol, adds 6N hydrochloric acid 33ml, stirred 24 hours in room temperature (about 20 ℃), every thereafter at a distance from plate of 2 little time points.When product point no longer changes and that assorted point of product below stopped reaction immediately when beginning to become big.Reaction solution is poured in the 500ml beaker, stirred and to add 3N aqueous sodium hydroxide solution 50ml down, add saturated sodium bicarbonate aqueous solution then pH value is transferred to 4-5, this reaction solution of concentrating under reduced pressure, debris is with ethyl acetate extraction 3 times, merging organic layer.Anhydrous sodium sulfate drying is used in water, saturated sodium-chloride washing successively.Filter, filtrate decompression concentrate crude product.Crude product dissolves with a small amount of methylene dichloride, and upper prop is used sherwood oil: ETHYLE ACETATE=10: 1 wash-outs; Concentrate white solid, this solid is dissolved with amount of ethyl acetate, add sherwood oil to tieing up big muddiness; Add smaller part this moment again and drip ETHYLE ACETATE and make solution becomes clarification, leave standstill then, separate out crystal.24 hours after-filtration, the filter cake drying under reduced pressure gets the 246mg product, yield 22.3%.
Get the rat random packet, 7 every group of drug group, 14 of negative control group.In preceding 40 hours gastric infusions of experiment, cut off the blood sampling of mouse tail, survey the clotting time.
Be dissolved in the 0.8%CMC solution by the reagent thing, The compounds of this invention and positive control survival dose are 20mg/kg, and irritating the stomach volume is 10ml/kg, the single gastric infusion.Negative control group waits the capacity solvent.
With the clotting time is index, carries out the t check, the significance of comparative group differences.
Receive the rat clotting time result of reagent thing to see table 1.
Table 1 rat docking clotting time experimental result
* each group of p＜0.05 * * p＜0.01 compares (t check) with negative control group
Embodiment 11
Get the rat random packet, 8 every group.If negative control group.Warnerin, the positive contrast medicine of warfarin.In preceding 40 hours gastric infusions of experiment, cut off the blood sampling of mouse tail, survey the clotting time.
Be dissolved in the 0.5%CMC solution by the reagent thing, The compounds of this invention and positive control survival dose are 10mg/kg, and irritating the stomach volume is 10ml/kg, the single gastric infusion.Negative control group waits the capacity solvent.With the clotting time is index, carries out the t check, the significance of comparative group differences.
Receive the rat clotting time result of reagent thing to see table 2.
Table 1 rat docking clotting time experimental result
* each group of p＜0.05 * * p＜0.01 compares (t check) with negative control group.
Claims (7)
1. compound or its pharmacy acceptable salt that following formula I is represented,
Formula I
In the formula: X is selected from and replaces or unsubstituted C6-C10 aryl;
Y is selected from the substituted C1-C10 alkyl of carboxamido-group;
R is selected from hydrogen, halogen, hydroxyl, replacement or unsubstituted C1-C10 alkyl, replacement or unsubstituted C1-C10 alkoxyl group;
Above-mentioned substituting group can be identical or different, is selected from hydrogen, halogen, hydroxyl, C1-C10 alkyl and C1-C10 alkoxyl group separately.
2. compound as claimed in claim 1 or its pharmacy acceptable salt is characterized in that said compound is selected from the compound that following formula is represented:
3. one kind is used for anticoagulant pharmaceutical composition, and said compsn comprises the described compound of claim 1 or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
4. pharmaceutical composition as claimed in claim 3 is characterized in that said pharmaceutical composition is the oral or non-oral dosage form of granula, pulvis, tablet, capsule, suppository, injection, emulsion, suspension-s or solution form.
5. pharmaceutical composition as claimed in claim 3 is characterized in that said pharmaceutical composition is the oral dosage form of syrup or tincture form.
6. the described compound of claim 1 or its pharmacy acceptable salt are in the purposes of preparation in the anticoagulation medicine.
7. purposes as claimed in claim 6 is characterized in that said anticoagulation medicine is used for prevention and treatment thrombotic disease; Prevention and treatment operation back or post-traumatic venous thrombosis; Prevention and treatment myocardial infarction; Prevention thromboembolism patient's complication and postoperative thrombus complication.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810041856A CN101654446B (en) | 2008-08-19 | 2008-08-19 | Anticoagulant compound, composition and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810041856A CN101654446B (en) | 2008-08-19 | 2008-08-19 | Anticoagulant compound, composition and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101654446A CN101654446A (en) | 2010-02-24 |
| CN101654446B true CN101654446B (en) | 2012-10-03 |
Family
ID=41708928
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200810041856A Active CN101654446B (en) | 2008-08-19 | 2008-08-19 | Anticoagulant compound, composition and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101654446B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106946897B (en) * | 2017-02-28 | 2018-10-23 | 牡丹江医学院 | A kind of drug that treating cholecystitis and its application |
| CN108623549A (en) * | 2017-03-16 | 2018-10-09 | 上海度德医药科技有限公司 | A kind of preparation method of Tecarfarin |
| CN111777590A (en) * | 2020-08-03 | 2020-10-16 | 连云港宏业化工有限公司 | New synthesis method of 2-thiophenecarboxaldehyde |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2427578A (en) * | 1945-04-02 | 1947-09-16 | Wisconsin Alumni Res Found | 3-substituted 4-hydroxycoumarin and process of making it |
| GB1025572A (en) * | 1963-08-26 | 1966-04-14 | Charles E Frosst & Company | New 3-substituted 4-hydroxycoumarins |
| US3574234A (en) * | 1966-12-13 | 1971-04-06 | Lipha | Derivatives of 4-hydroxy coumarine |
| CN1950353A (en) * | 2004-04-08 | 2007-04-18 | ARYx医疗有限公司 | Materials and methods for treating coagulation disorders |
-
2008
- 2008-08-19 CN CN200810041856A patent/CN101654446B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2427578A (en) * | 1945-04-02 | 1947-09-16 | Wisconsin Alumni Res Found | 3-substituted 4-hydroxycoumarin and process of making it |
| GB1025572A (en) * | 1963-08-26 | 1966-04-14 | Charles E Frosst & Company | New 3-substituted 4-hydroxycoumarins |
| US3574234A (en) * | 1966-12-13 | 1971-04-06 | Lipha | Derivatives of 4-hydroxy coumarine |
| CN1950353A (en) * | 2004-04-08 | 2007-04-18 | ARYx医疗有限公司 | Materials and methods for treating coagulation disorders |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101654446A (en) | 2010-02-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102617567A (en) | Lactam-containing compounds and derivatives thereof as factor Xa inhibitors | |
| KR20100016428A (en) | Combination anticoagulant therapy with a compound that acts as a factor xa inhibitor | |
| CN101654427B (en) | Anticoagulant compound, composition and application thereof | |
| JP2013536220A (en) | Methods for treating or preventing thrombosis or emboli | |
| CN101654446B (en) | Anticoagulant compound, composition and application thereof | |
| CN101535304A (en) | Serine hydrolase inhibitors | |
| JPH0471077B2 (en) | ||
| WO2010006189A2 (en) | Small-molecule inhibitors of hif and angiogenesis | |
| KR100352425B1 (en) | Pharmaceutical compositions containing tetrahydroisoquinoline compounds | |
| CN102459215A (en) | 3-(4-aminophenyl)-2-furancarboxylic acid derivative and pharmaceutically acceptable salt thereof | |
| KR20110026311A (en) | Novel salts of entecavir | |
| CN101654441B (en) | Anticoagulant compound, composition and application thereof | |
| CN101654405A (en) | Anticoagulant compound, composition and application thereof | |
| EP1290010A1 (en) | Pyridine-2-yl-aminoalkyl carbonyl glycyl-$g(b)-alanine and derivatives thereof | |
| CN108484550B (en) | Sphaelactone derivative and preparation method and application thereof | |
| WO2009150668A1 (en) | Dihydropyridimidinone compounds for the treatment of cardiovascular diseases and process for preparing the same | |
| CA2398186A1 (en) | Therapeutic agent for reperfusion injury comprising integrin .alpha.v.beta.3 antagonists | |
| CN103193792A (en) | New compound for treating ischemic cardiovascular and cerebrovascular diseases | |
| TW593314B (en) | Benzisoxazolyl-pyrazole compounds, intermediates therefor, processes for making the same, and pharmaceutical composition useful as a factor XA inhibitor comprising the same | |
| CN103420985B (en) | As the dabigatran ester derivative and its production and use of prodrug | |
| AU731173B2 (en) | Crystalline pharmaceutical product | |
| CN102066326A (en) | Pyridone compound | |
| RU1779246C (en) | Process for producing derivatives of 1-acyl-2,3-dihydro-4 (-1-) quinolinon-4-oxyma-0-sulfonic acid or salts thereof | |
| CN104098647B (en) | Argatroban analog and preparation method thereof and medical usage | |
| AU2021208762A1 (en) | Novel compounds as inhibitors of PCSK9 |
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 | ||
| C56 | Change in the name or address of the patentee |
Owner name: SHANGHAI SINE PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME: SINE PHARMACEUTICAL FACTORY CO., LTD. |
|
| CP03 | Change of name, title or address |
Address after: 201206 Pudong New Area new Jinqiao Road, Shanghai, No. 905 Patentee after: Shanghai Sine Pharmaceutical Co., Ltd. Address before: 201206 No. 787-791, Tang Lu, Shanghai, Pudong New Area Patentee before: Sine Pharmaceutical Factory Co., Ltd. |
|
| C56 | Change in the name or address of the patentee | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 201206 Pudong New Area new Jinqiao Road, Shanghai, No. 905 Patentee after: Shanghai Xinyi Pharmaceutical Co. Ltd.. Address before: 201206 Pudong New Area new Jinqiao Road, Shanghai, No. 905 Patentee before: Shanghai Sine Pharmaceutical Co., Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20180731 Address after: 253100 No. 1 Xingping Road, Pingyuan County, Dezhou, Shandong Patentee after: Shandong Xinyi Pharmaceutical Co., Ltd. Address before: No. 905, new Jinqiao Road, Pudong New Area, Shanghai Patentee before: Shanghai Xinyi Pharmaceutical Co. Ltd.. |