CN104356059B - Trans cvclohexvl alkyl amide compound containing halogenated pyridyl and purposes - Google Patents
Trans cvclohexvl alkyl amide compound containing halogenated pyridyl and purposes Download PDFInfo
- Publication number
- CN104356059B CN104356059B CN201410635589.2A CN201410635589A CN104356059B CN 104356059 B CN104356059 B CN 104356059B CN 201410635589 A CN201410635589 A CN 201410635589A CN 104356059 B CN104356059 B CN 104356059B
- Authority
- CN
- China
- Prior art keywords
- compound
- present
- purposes
- compound containing
- formula
- 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.)
- Expired - Fee Related
Links
- 0 ***1*c(N2CCNCC2)ccc1 Chemical compound ***1*c(N2CCNCC2)ccc1 0.000 description 2
- CMMHXWVCRKUMNN-UHFFFAOYSA-N CC(C)(C)C(CC1)CCC1C(N(CC1)CCN1c1cc(Cl)ccn1)=O Chemical compound CC(C)(C)C(CC1)CCC1C(N(CC1)CCN1c1cc(Cl)ccn1)=O CMMHXWVCRKUMNN-UHFFFAOYSA-N 0.000 description 1
- DSMHEHSOYGGLSP-UHFFFAOYSA-N CC(C)(C)C(CC1)CCC1C(N(CC1)CCN1c1nccc(F)c1)=O Chemical compound CC(C)(C)C(CC1)CCC1C(N(CC1)CCN1c1nccc(F)c1)=O DSMHEHSOYGGLSP-UHFFFAOYSA-N 0.000 description 1
- QVQKEGYITJBHRQ-UHFFFAOYSA-N CC(C)(C)C(CC1)CCC1C(O)=O Chemical compound CC(C)(C)C(CC1)CCC1C(O)=O QVQKEGYITJBHRQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to the drug world relevant to thrombotic diseases.Specifically, the present invention relates to a class containing PAR 1 antagonist of halogenated pyridyl isostructural trans cyclohexane amide structure, its preparation method and their application in preparation treatment thrombotic diseases medicine.Wherein, R is selected from C1‑C3Alkyl, F, Cl, Br, I substituent.
Description
Technical field
The present invention relates to the drug world relevant to thrombus disease.Specifically, the present invention relates to thrombotic diseases is had
One class of therapeutic action contains PAR-1 antagonist and the preparation side thereof of halogenated pyridyl isostructural trans cyclohexane amide structure
Method, containing they pharmaceutical composition and in purposes pharmaceutically.
Background technology
Proteinase activated receptors 1 (Protease Activated Acceptor-1, PAR-1) is the anti-blood found recently
The novel targets of platelet class antithrombotic reagent.Proteinase activated receptors 1 is again thrombin receptor, after fibrin ferment is activated by coagulation cascade
In blood platelet thus activate blood platelet by PAR-1 receptor acting, cause platelet aggregation thus cause thrombus and blood coagulation.PAR-
Rich in platelet component in 1 thrombus caused, it it is the main reason of arterial thrombus.PAR-1 antagonist can block thrombin activation
Blood platelet, thus interruption artery thrombosis, may be used for treating acute coronary artery disease (Acute Coronary
Syndrome).Several PAR-1 inhibitor has been had to be in clinical research (Chackalamannil S., Thrombin
Receptor(Protease Activated Receptor-1)Antagonists as Potent Antithrombotic
Agents with Strong Antiplatelet Effects, J.Med.Chem., 2006,49 (18), 5389-5403).
The medicine being traditionally used for preventing and treating thrombotic diseases is divided three classes.The first kind is anticoagulation class, is divided into direct blood coagulation
Enzyme inhibitor and indirect thrombin inhibitor, such medicine suppresses thrombus shape by the different links acting on coagulation cascade
Become, there are the various thrombotic effects of suppression, such as vitamin K antagon and Xa factor inhibitor etc.；Equations of The Second Kind is that anti-blood is little
Plate class, such as COX-1 inhibitor and adp receptor antagonist etc., such medicine is mainly used in preventing and treating arterial thrombus；3rd class is fiber
Protein dissolution agent, is mainly used in lysed blood the fibrin formed.
Mostly antiplatelet drug is traditional arterial thrombus protective agents, such as clopidogrel and aspirin etc..These medicines
The shortcoming of thing is that bleeding risk is bigger.And as the PAR-1 antagonist of newfound antiplatelet class antithrombotic reagent, then have
Having less bleeding risk, therefore this compounds can be as the most promising medicine for the treatment of arterial thrombus.
The invention discloses the class PAR-1 antagonist containing halogenated pyridyl isostructural trans cyclohexane amide structure,
They may be used for preparing the medicine of anti-arterial thrombus disease.
Summary of the invention
It is an object of the present invention to provide a kind of have good anti-thrombosis activity have compounds of formula I and
Its pharmaceutically acceptable salt.
It is a further object to provide preparation and there is compounds of formula I and pharmaceutically acceptable salt thereof
Method.
It is also another object of the present invention to provide containing compounds of formula I and pharmaceutically acceptable salt as having
Effect composition, and one or more pharmaceutically acceptable carriers, excipient or the Pharmaceutical composition of diluent, and in treatment
Application in terms of arterial thrombus.
In conjunction with the purpose of the present invention, present invention is specifically described.
The present invention has compounds of formula I and has a following structural formula:
Wherein, R is selected from C1-C3Alkyl, F, Cl, Br, I substituent.
Further, preferably following have compounds of formula I,
Further, preferably following have compounds of formula I,
Compound of formula I of the present invention synthesizes by the following method:
Compound II and compound III reacts in the presence of condensing agent, obtains product I.Described condensing agent selected from DCC (N,
N '-dicyclohexyl carbodiimide), EDC (N-ethyl-N '-dimethylamino carbodiimides), CDI (carbonyl dimidazoles).
The pharmaceutically acceptable salt of compound of formula I of the present invention, includes, but are not limited to and various inorganic acids such as salt
The salt that acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid etc. are formed, also includes and various organic acids such as acetic acid, butanedioic acid, maleic acid, apple
The salt that tartaric acid and various amino acid etc. are formed.
Compound of Formula I of the present invention has the antagonism of PAR-1, can be used for preparing antithrombotic as active ingredient
The medicine of aspect.The activity of compound of Formula I of the present invention is verified by external model.
The compound of Formula I of the present invention is effective in comparatively wide dosage range.The dosage that such as every day takes is about
In the range of 1mg-500mg/ people, it is divided into once or is administered for several times.The actual dosage taking compound of Formula I of the present invention can be by curing
Take root and determine according to relevant situation.These situations include: the condition of patient, method of administration, the age, body weight, right
The individual reaction of medicine, the order of severity etc. of symptom.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that following embodiment is only for
Illustrate, and be not intended to limit the present invention.Those skilled in the art all should according to the various changes that the teachings of the present invention is made
Within the protection domain required by the application claim.
The preparation of embodiment 1 compound I-1
Raw material: commercially available or self-control.
In one 100mL round-bottomed flask, add 1.84g (10mmol) compound II, 1.98g (10mmol) compound III-
1 and the 20mL THF being dried, gained mixture stirs under ice-water bath cools down, and after adding 2.48g (12mmol) DCC, continues in room
It is stirred overnight under temperature.TLC display reaction completes.
Reactant mixture pours in frozen water, stirring, extracts with the dichloromethane of 50mL × 3, merges extraction organic phase, uses
Saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and boils off solvent on a rotary evaporator, and the residue column chromatography obtained purifies,
Obtain product I-1, white solid, ESI-MS, m/z=365 ([M+H]+)。
Embodiment 2-8
With reference to the method for embodiment 1, synthesize the following compounds with formula I.
The suppression test of embodiment 9 extracorporeal platelet aggregation
In 96 orifice plates, the platelet aggregation induced at TRAP (Glycoprotein) concentrates the pharmacology carrying out material
Test.Syringe is previously added the sodium citrate solution of 3.13%, the then blood of suction 20mL healthy volunteer,
Under 1500g centrifugal 20 minutes, will be enriched in hematoblastic blood plasma (PRP) separate and with 1 μ L PGE1 solution (500 μ g/mL's
Ethanol solution) amount of/mL PRP processes.After at room temperature hatching 5 minutes, it is centrifuged under 1200g 20 minutes to remove
Leucocyte-removing.PRP without leucocyte is transferred to 5mL/ part in the PP pipe of 15mL in batches, and centrifugal under 3600g make blood
Platelet precipitates.Then, drain upper plasma, the pellet platelets deriving from 5mL PRP is suspended in 1mL Tyrode again
(120mM NaCl, 2.6mM KCl, 12mM NaHCO3, 0.39mM NaH2PO4, 10mM HEPES, 0.35%BSA, 5.5mM Portugal
Grape sugar, pH=7.4) in, and regulate the platelet count to 3 × 105/ μ L with Tyrode.This for 13mL cell suspension is used
The 10mM CaCl of 866 μ L2Solution processes, and is drawn in 96 orifice plates, in the hole of 96 orifice plates with the amount of every hole 120 μ L
Add 15 μ L materials to be tested in advance.At room temperature dark is hatched 30 minutes, add 15 μ L TRAP solution (70-100 μM)
As activator, vibrate 20 minutes at 37 DEG C in SpectraMax, under 650nm, note down dynamics, calculate negative control
(tyrode/DMSO) and the TG-AUC of positive control (15 μ L activators/DMSO), and difference is set to 100%.By to be measured
Examination compound aspirates with the form of serial dilution thing, is measured in duplicate, the same AUC measuring each material concentration, meter
Calculate AUC compared with the control and suppress %.IC is calculated according to 4 parametric equations by nonlinear regression analysis by this suppression %50Value.
Following table gives result.
| Compound | The suppression IC of platelet aggregation50(μM) |
| Compound I-1 | 0.9 |
| Compound I-2 | 4.1 |
| Compound I-3 | 3.5 |
| Compound I-4 | 3.2 |
| Compound I-5 | 2.0 |
| Compound I-6 | 4.7 |
| Compound I-7 | 4.2 |
| Compound I-8 | 3.8 |
As can be seen from the above table, the compound of the present invention all shows inhibitory action in platelet aggregation test.
Claims (3)
1. following compounds,
2. compound described in claim 1, selected from following compounds:
3. compound of Formula I defined in any one of claim 1-2 and pharmaceutically acceptable salt preparation treatment blood
Purposes in terms of bolt medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410635589.2A CN104356059B (en) | 2014-11-02 | 2014-11-02 | Trans cvclohexvl alkyl amide compound containing halogenated pyridyl and purposes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410635589.2A CN104356059B (en) | 2014-11-02 | 2014-11-02 | Trans cvclohexvl alkyl amide compound containing halogenated pyridyl and purposes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104356059A CN104356059A (en) | 2015-02-18 |
| CN104356059B true CN104356059B (en) | 2016-08-24 |
Family
ID=52523396
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410635589.2A Expired - Fee Related CN104356059B (en) | 2014-11-02 | 2014-11-02 | Trans cvclohexvl alkyl amide compound containing halogenated pyridyl and purposes |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104356059B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006057868A1 (en) * | 2004-11-29 | 2006-06-01 | Eli Lilly And Company | Antithrombotic diamides |
| CN104072438A (en) * | 2014-07-23 | 2014-10-01 | 张远强 | Di-alkoxy substituted tetrazole acetophenone compound, as well as preparation method and application thereof |
| CN104086503A (en) * | 2014-07-23 | 2014-10-08 | 张远强 | PAR (Protease Activated Receptor)-1 antagonist and application thereof |
-
2014
- 2014-11-02 CN CN201410635589.2A patent/CN104356059B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006057868A1 (en) * | 2004-11-29 | 2006-06-01 | Eli Lilly And Company | Antithrombotic diamides |
| CN104072438A (en) * | 2014-07-23 | 2014-10-01 | 张远强 | Di-alkoxy substituted tetrazole acetophenone compound, as well as preparation method and application thereof |
| CN104086503A (en) * | 2014-07-23 | 2014-10-08 | 张远强 | PAR (Protease Activated Receptor)-1 antagonist and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| N-Acyl-N0-arylpiperazines as negative allosteric modulators of mGlu1:Identification of VU0469650, a potent and selective tool compound with CNS exposure in rats;Kimberly M.Lovell等;《Bioorganic & Medicinal Chemistry Letters》;20131231;第23卷;第3713-3718页 * |
| S. P. Webster et al. Discovery and biological evaluation of adamantly amide 11β-HSD1 inhibitors;S. P. Webster et al.;《Bioorg. Med. Chem. Lett.》;20070225;pp2838-2843 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104356059A (en) | 2015-02-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104072436A (en) | Para-position substituted tetrazole acetophenone compound, preparation method and application | |
| CN104529927B (en) | One class is containing oxadiazoles sulfoxide compound, the Preparation Method And The Use of halogeno-benzene | |
| CN104098520A (en) | Phenyl triazole schiff base compound as well as preparation method and application thereof | |
| CN104086503B (en) | PAR-1 antagonist and uses thereof | |
| CN104072439A (en) | Halogen-substituted four nitrogen azole acetophenone compound,preparation method and application thereof | |
| CN104072437A (en) | Disubstituted tetrazole acetophenone compound and preparation method and use thereof | |
| CN104086500B (en) | A kind of PAR-1 antagonist and uses thereof | |
| CN104356059B (en) | Trans cvclohexvl alkyl amide compound containing halogenated pyridyl and purposes | |
| CN104356058B (en) | Trans cvclohexvl alkyl amide compound containing alkoxy pyridines and purposes | |
| CN104356060B (en) | The trans cvclohexvl alkyl amide compound of 2-pyridine radicals and purposes | |
| CN104326974B (en) | The trans cvclohexvl alkyl amide compound of 4 pyridine radicals and purposes | |
| CN104356094B (en) | Trans cvclohexvl alkyl amide compound, its preparation method and in purposes pharmaceutically | |
| CN104086496B (en) | A kind of antithrombotic compound, Preparation Method And The Use | |
| CN104356093B (en) | Trans cvclohexvl alkyl amide compound containing halogenophenyl and purposes | |
| CN104447624B (en) | The trans cvclohexvl alkyl amide compound of nitrile group-containing phenyl and purposes | |
| CN104496924B (en) | Halobenzene diene tetrazole compound, Preparation Method And The Use | |
| CN104356095B (en) | The trans cvclohexvl alkyl amide compound of alkoxyl phenyl replacement and purposes | |
| CN104496925B (en) | Diene tetrazole compound, Preparation Method And The Use | |
| CN104513212B (en) | Oxadiazoles sulfoxide compound, the Preparation Method And The Use of one class nitrobenzene-containing | |
| CN104387341B (en) | A kind of trans cvclohexvl alkyl amide compound and purposes | |
| CN104496927B (en) | Diene tetrazole halobenzene compounds, Preparation Method And The Use | |
| CN104496923B (en) | Oil of mirbane diene tetrazole compound, Preparation Method And The Use | |
| CN104496922B (en) | Itrile group benzene diene tetrazole compound, Preparation Method And The Use | |
| CN104478819B (en) | Diene tetrazole amino benzenes compounds, Preparation Method And The Use | |
| CN104529930B (en) | One class nitrile group-containing Ben oxadiazole sulfoxide compound, Preparation Method And The Use |
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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160824 Termination date: 20171102 |