CN104356060B - The trans cvclohexvl alkyl amide compound of 2-pyridine radicals and purposes - Google Patents
The trans cvclohexvl alkyl amide compound of 2-pyridine radicals and purposes Download PDFInfo
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- CN104356060B CN104356060B CN201410635670.0A CN201410635670A CN104356060B CN 104356060 B CN104356060 B CN 104356060B CN 201410635670 A CN201410635670 A CN 201410635670A CN 104356060 B CN104356060 B CN 104356060B
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- compound
- pyridine radicals
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- amide compound
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- 0 C=*(CC1)CC*1C1CC1 Chemical compound C=*(CC1)CC*1C1CC1 0.000 description 3
- GZRKXKUVVPSREJ-UHFFFAOYSA-N C(C1)NCCN1c1ccccn1 Chemical compound C(C1)NCCN1c1ccccn1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 description 1
- AFZAAIDHQAQXHP-UHFFFAOYSA-N CC(C)(C)C(CC1)CCC1C(N(CC1)CCN1c1ncccc1)=O Chemical compound CC(C)(C)C(CC1)CCC1C(N(CC1)CCN1c1ncccc1)=O AFZAAIDHQAQXHP-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
- BWJSSYBIZVGKBG-UHFFFAOYSA-N CC(C)(C)C(CC1)CCC1C(OC)=O Chemical compound CC(C)(C)C(CC1)CCC1C(OC)=O BWJSSYBIZVGKBG-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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to the drug world relevant to thrombotic disease.Specifically, the present invention relates to PAR 1 antagonist of the trans cyclohexane amide structure containing 2 pyridine radicals of a kind of formula (I) structure and the application in preparation treatment thrombotic disease medicine.
Description
Technical field
The present invention relates to the drug world relevant to thrombus disease.Specifically, the present invention relates to thrombotic disease is had
The PAR-1 antagonist of a kind of trans cyclohexane amide structure containing 2-pyridine radicals of therapeutical effect and at preparation treatment thrombotic
Application in disease medicament.
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 thrombin is activated by coagulation cascade
In platelet thus activate platelet by PAR-1 receptor acting, cause platelet aggregation thus cause thrombosis and blood coagulation.PAR-
Rich in platelet component in 1 thrombosis caused, it it is the main reason of arterial thrombus.PAR-1 antagonist can block thrombin activation
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 disease 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 thrombosis 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 PAR-1 antagonist containing 2-pyridine radicals trans cyclohexane amide structure of a kind of formula (I) structure,
It 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 the knot of the trans cyclohexane amide containing 2-pyridine radicals of a kind of formula (I) structure
The compound of structure and pharmaceutically acceptable salt.
It is also another object of the present invention to provide containing compounds of formula I and pharmaceutically acceptable salt 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 the compound of Formulas I and has a following structural formula:
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 mineral acids such as salt
The salt that acid, sulphuric acid, nitric acid, phosphoric acid, hydrobromic acid etc. are formed, also includes and various organic acid such as acetic acid, succinic acid, maleic acid, Herba Marsileae Quadrifoliae
The salt that fruit acid and various aminoacid etc. are formed.
Compound of formula I of the present invention has the antagonism of PAR-1, can be used for preparing antithrombotic side as effective ingredient
The medicine in face.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 about exists
In the range of 1mg-500mg/ people, it is divided into once or is administered for several times.The actual dosage taking formula I can be by doctor's root
Determine according to relevant situation.These situations include: the condition of patient, route of administration, the age, body weight, to medicine
Individual reaction, 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 the compounds of this invention I
In one 100mL round-bottomed flask, add 1.84g (10mmol) compound II, 1.62g (10mmol) compound III
The THF being dried with 20mL, 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 facies, uses
Saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and boils off solvent on a rotary evaporator, the residue column chromatography purification obtained,
Obtain product I, white solid, ESI-MS, m/z=330 ([M+H]+)。
The preparation of embodiment 2 control compounds I-2
For contrasting further the drug effect of this compound, this invention describes following formula control compounds I-2 (noval chemical compound, still
Undisclosed) and preparation method thereof and pharmacological datum:
Its preparation method is as follows:
In one 100mL round-bottomed flask, add 1.84g (10mmol) compound II, 1.26g (10mmol) compound III-
2 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 facies, uses
Saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and boils off solvent on a rotary evaporator, the residue column chromatography purification obtained,
Obtain product I-2, white solid.ESI-MS, m/z=293 ([M+H]+)。
Embodiment 3 extracorporeal platelet aggregation inhibition test
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 leukocyte 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 agonist, vibrate 20 minutes at 37 DEG C in SpectraMax, under 650nm, note down kinetics, calculate negative control
(tyrode/DMSO) and the area under curve of positive control (15 μ L agonist/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.
As can be seen from the above table, the compound of the present invention all shows inhibitory action in platelet aggregation test, and just
For drug effect, the compounds of this invention I is better than control compounds I-2.
Claims (4)
1. there is compound and the pharmaceutically acceptable salt thereof of Formulas I structure,
2. the method for compound described in preparation claim 1,
Compound II and compound III reacts in the presence of condensing agent, obtains product I.
3. the method for compound described in preparation claim 2, (N, N '-dicyclohexyl carbonization two is sub-selected from DCC for described condensing agent
Amine), EDC (N-ethyl-N '-dimethylamino carbodiimides), CDI (carbonyl dimidazoles).
4. compound described in claim 1 and pharmaceutically acceptable salt use in terms of preparation treatment thrombotic medicine
On the way.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410635670.0A CN104356060B (en) | 2014-11-02 | 2014-11-02 | The trans cvclohexvl alkyl amide compound of 2-pyridine radicals and purposes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410635670.0A CN104356060B (en) | 2014-11-02 | 2014-11-02 | The trans cvclohexvl alkyl amide compound of 2-pyridine radicals and purposes |
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| Publication Number | Publication Date |
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| CN104356060A CN104356060A (en) | 2015-02-18 |
| CN104356060B true CN104356060B (en) | 2016-08-31 |
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| CN201410635670.0A Expired - Fee Related CN104356060B (en) | 2014-11-02 | 2014-11-02 | The trans cvclohexvl alkyl amide compound of 2-pyridine radicals and purposes |
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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 CN201410635670.0A patent/CN104356060B/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 |
|---|
| Discovery and biological evaluation of adamantly amide 11β-HSD1 inhibitors;S. P. Webster et al.;《Bioorg. Med. Chem. Lett.》;20070225;第17卷;pp2838-2843 * |
| 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 * |
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| CN104356060A (en) | 2015-02-18 |
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