CN102649787A - (benzimidazole-2-yl)pyridine derivative and application thereof to preparation of anticoagulant medicines - Google Patents
(benzimidazole-2-yl)pyridine derivative and application thereof to preparation of anticoagulant medicines Download PDFInfo
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- CN102649787A CN102649787A CN2011100427925A CN201110042792A CN102649787A CN 102649787 A CN102649787 A CN 102649787A CN 2011100427925 A CN2011100427925 A CN 2011100427925A CN 201110042792 A CN201110042792 A CN 201110042792A CN 102649787 A CN102649787 A CN 102649787A
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- prodrug
- hydrate
- acceptable salt
- formula
- benzoglyoxaline
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- 0 C[n](c(CNc(cc1)ccc1C(N)=N)nc1c2)c1ccc2C(N(C(*)(*)CC(O)=O)c1ccccn1)=O Chemical compound C[n](c(CNc(cc1)ccc1C(N)=N)nc1c2)c1ccc2C(N(C(*)(*)CC(O)=O)c1ccccn1)=O 0.000 description 1
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Abstract
The invention relates to a novel (benzimidazole-2-yl)pyridine derivative and an application thereof to preparation of anticoagulant medicines. The (benzimidazole-2-yl)pyridine derivative is an ideal thrombin inhibitor, and can be used for treating and preventing or treating thrombosis and other indications including auricular fibrillation, acute coronary syndrome, acute symptomatic phlebothrombosis, cerebral arterial thrombosis and the like.
Description
Technical field
The present invention relates to the benzoglyoxaline pyridine derivate and prevent and/or treat the purposes in the anticoagulation medicine in preparation.
Background technology
Along with the variation of human lives's Working environment, the incidence of thrombotic diseases increases year by year, the disease that myocardial infarction and cerebral infarction are respectively current lethality rates, disability rate is the highest.Along with the aging of population, the increase of cardiovascular disease incidence rate, the demand of anticoagulant is constantly increased, hope that the novel anti blood-clotting agent will bring the more benefit to the patient more.
Zymoplasm is an extracellular Insulin-Like Tryase, in coagulation process, has vital role, and on the one hand, it can make the Fibrinogen cracking become scleroproein, and the latter participates in constituting the hard clot suppository matrix; On the other hand, its ability induced platelet activation and gathering, and then cause a series of secondary coagulation cascades reactions.Directly thrombin inhibitors combines with the zymoplasm reversibility, and combination speed is very fast, and the transformation period is short, and effect is not influenced by patient age, sex and renal function, no drug drug interaction.Along with people's deepens continuously to the understanding of direct thrombin inhibitors, and its clinical application increases gradually, is mainly used in the prevention Ischemic Stroke, also can be used for preventing simultaneously preventing to send out ischemic behind other arterial thrombosis property diseases, the PCI again.Such medicine is little to normal coagulation function influence, and hemorrhage risk is less, and security is higher.
Summary of the invention
Technical problem to be solved by this invention provides a kind of benzoglyoxaline pyridine compounds and their; It is the direct thrombin inhibitors of ideal; Can be used for prevention or treatment thrombosis and other indications and comprise atrial fibrillation, acute coronary syndrome, acute symptomatic venous thrombosis and cerebral infarction, also can be used for treating simultaneously prevention or the treatment tumour indication relevant with the zymoplasm function.
For solving above technical problem, the present invention takes following technical scheme:
Compound or pharmaceutically acceptable salt thereof, hydrate or prodrug with logical formula I:
In the above-mentioned formula I:
R
01Represent C
1～C
12Saturated alkyl or C
2～C
12Unsaturated thiazolinyl or alkynyl or Ene alkynyl base;
R
02Be any prodrug group;
R
03For-CO
2H ,-C (NH) NH
2,-CH
3N
2O ,-CHN
4,-C
2H
2N
3,-C
2HN
2O
2Or on their bases any prodrug group of bonded.
Prodrug group described in the present invention refers to outside organism or human body, not have activity or activity very little, and under the effect of organism or the intravital enzyme of people, regains active group.In the present invention, the prodrug group includes but not limited to following group :-C
nH
2n+1-CH
2CF
3-CH
2CF
2C
nH
2n+1-CH
2CHFC
nH
2n+1-CH
2C
6H
5-CH
2C
6H
4X;-CH
2C
6H
3X
2-CH
2C
5H
4N;-CH
2C
3H
3N
2-CH
2C
3H
2N
3-CH
2C
5H
3NX;-CH
2C
4H
2NX
2-C
nH
2n-5O
3-C
nH
2nN;-C
nH
2nNO;-C
nH
2n+1N
2-C
nH
2n+1N
2O;-C
nH
2n+2N
3-CHN
4-C
nH
2n+2N
3O;-C
nH
2nOCOOC
nH
2n+1-C
nH
2nOCOOC
nH
2n-1-C
nH
2nOCOC
nH
2nNH (C
nH
2n+1);-C
nH
2nOCOC
nH
2nN (C
nH
2n+1)
2-C
nH
2nOCOC
nH
2nNH (C
nH
2n-1);-C
nH
2nOCOC
nH
2nN (C
nH
2n-1)
2-C
nH
2nCOC
nH
2nNH (COC
nH
2n+1);-C
nH
2nCOC
nH
2nNH (COC
nH
2n-1);-C
nH
2nN (C
nH
2n+1) C
nH
2n+1COOH;-C
nH
2nOPO (OH)
2, wherein X is F, Cl, Br, OC
mH
2m+1, SC
mH
2m+1Or NHC
mH
2m+1, n, m are the integer between 1～8 independently.
According to a preferred aspect of the present invention, in the formula I, R
01Represent C
1～C
12Saturated alkyl or C
2～C
12Unsaturated thiazolinyl or alkynyl or Ene alkynyl base; R
03For-CO
2H ,-C (NH) NH
2,-CH
3N
2O ,-CHN
4,-C
2H
2N
3And-C
2HN
2O
2In a kind of.More preferably, R
01Represent C
1～C
6Saturated alkyl.
Be according to particular compound more of the present invention below.
Among the present invention, mentioned alkyl, thiazolinyl, alkynyl can not be straight chain, side chain or ring-type when having special definition.
According to the present invention, described pharmacologically acceptable salt includes but not limited to hydrochloride, phosphoric acid salt, vitriol, acetate, PHENRAMINE MALEATE, benzene sulfonate, toluenesulfonate, fumarate, tartrate etc.
Benzoglyoxaline pyridine derivate provided by the invention; Its pharmacologically acceptable salt; Hydrate or prodrug are a kind of direct thrombin inhibitorss; Can be used for treatment prevention or treatment thrombosis and other indications and comprise that atrial fibrillation, acute coronary syndrome, acute symptomatic venous thrombosis and ischemic cerebral apoplexy are medium, also can be used for treating simultaneously prevention or the treatment tumour indication relevant with the zymoplasm function.
The invention still further relates to meta-bolites that above-mentioned benzoglyoxaline pyridine derivate or its pharmacologically acceptable salt, hydrate or prodrug form in any form and meta-bolites and prevent and/or treat the purposes in the medicine of the indication relevant with the zymoplasm function in preparation.
The present invention also relates to one or more the pharmaceutical composition that includes in the above-claimed cpd simultaneously, this pharmaceutical composition can be used for preventing and/or or treatment and body in the relevant indication of uric acid complex functionality.
Because the enforcement of above technical scheme, the present invention compared with prior art has following advantage:
Compound first pass effect of the present invention is less, and effectively bioavailability is high, and it is few when the treatment indication relevant with the zymoplasm function, to have a using dosage, the advantage that spinoff is little.
Embodiment
Below in conjunction with specific embodiment the present invention is done further detailed explanation, but the present invention is not limited to following examples.
Embodiment 1
The compound that present embodiment provides a kind of formula II to represent:
Embodiment 2
The compound that present embodiment provides a kind of formula III to represent:
Embodiment 3
The compound that present embodiment provides a kind of formula IV to represent:
Embodiment 4
Present embodiment provides the compound of a kind of formula (V) expression:
The foregoing description only is explanation technical conceive of the present invention and characteristics, and its purpose is to let the personage who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalences of doing based on spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (10)
1. the benzoglyoxaline pyridine derivate or its pharmacologically acceptable salt, hydrate or the prodrug that have logical formula I:
It is characterized in that: in the said formula I:
R
01Represent C
1～C
12Saturated alkyl or C
2～C
12Unsaturated thiazolinyl or alkynyl or Ene alkynyl base;
R
02Be any prodrug group;
R
03For-CO
2H ,-C (NH) NH
2,-CH
3N
2O ,-CHN
4,-C
2H
2N
3,-C
2HN
2O
2Or on their bases any prodrug group of bonded.
2. benzoglyoxaline pyridine derivate according to claim 1 or its pharmacologically acceptable salt, hydrate or prodrug is characterized in that: in the formula I, and R
01Represent C
1～C
12Saturated alkyl or C
2～C
12Unsaturated thiazolinyl or alkynyl or Ene alkynyl base; R
03For-CO
2H ,-C (NH) NH
2,-CH
3N
2O ,-CHN
4,-C
2H
2N
3Or-C
2HN
2O
2
3. benzoglyoxaline pyridine derivate according to claim 1 or its pharmacologically acceptable salt, hydrate or prodrug is characterized in that: R
01Represent C
1～C
6Saturated alkyl.
4. benzoglyoxaline pyridine derivate according to claim 1 or its pharmacologically acceptable salt, hydrate or prodrug is characterized in that: said compound be formula II, formula III, formula IV and formula (V) expression compound in a kind of.
In the claim 1 to 4 the described compound or pharmaceutically acceptable salt thereof of each claim, hydrate or prodrug as the purposes of thrombin inhibitors.
6. the described compound or pharmaceutically acceptable salt thereof of each claim, hydrate or prodrug prevent and/or treat the purposes in the medicine of the indication relevant with the zymoplasm function in preparation in the claim 1 to 4.
7. purposes according to claim 6 is characterized in that: the said indication relevant with the zymoplasm function comprises thrombosis, atrial fibrillation, acute coronary syndrome, acute symptomatic venous thrombosis and cerebral infarction.
8. the meta-bolites that the described compound or pharmaceutically acceptable salt thereof of each claim, hydrate or prodrug form in any form in the claim 1 to 4.
9. the described meta-bolites of claim 8 prevents and/or treats the purposes in the medicine of the indication relevant with the zymoplasm function in preparation.
10. the pharmaceutical composition that has comprised the described compound or pharmaceutically acceptable salt thereof of each claim, hydrate or prodrug in one or more claims 1 to 4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100427925A CN102649787A (en) | 2011-02-23 | 2011-02-23 | (benzimidazole-2-yl)pyridine derivative and application thereof to preparation of anticoagulant medicines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100427925A CN102649787A (en) | 2011-02-23 | 2011-02-23 | (benzimidazole-2-yl)pyridine derivative and application thereof to preparation of anticoagulant medicines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102649787A true CN102649787A (en) | 2012-08-29 |
Family
ID=46691917
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011100427925A Pending CN102649787A (en) | 2011-02-23 | 2011-02-23 | (benzimidazole-2-yl)pyridine derivative and application thereof to preparation of anticoagulant medicines |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102649787A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964374A (en) * | 2012-11-28 | 2013-03-13 | 玉林师范学院 | Benzimidazole pyridine complex and method for preparing same |
-
2011
- 2011-02-23 CN CN2011100427925A patent/CN102649787A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964374A (en) * | 2012-11-28 | 2013-03-13 | 玉林师范学院 | Benzimidazole pyridine complex and method for preparing same |
| CN102964374B (en) * | 2012-11-28 | 2015-10-28 | 玉林师范学院 | A kind of benzoglyoxaline pyridines title complex and preparation method thereof |
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Application publication date: 20120829 |