CN104356058B - Trans cvclohexvl alkyl amide compound containing alkoxy pyridines and purposes - Google Patents
Trans cvclohexvl alkyl amide compound containing alkoxy pyridines and purposes Download PDFInfo
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- CN104356058B CN104356058B CN201410635580.1A CN201410635580A CN104356058B CN 104356058 B CN104356058 B CN 104356058B CN 201410635580 A CN201410635580 A CN 201410635580A CN 104356058 B CN104356058 B CN 104356058B
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- NYZTXWUIESLKRZ-UHFFFAOYSA-N CC(C)(C)C(CC1)CCC1C(N(CC1)CCN1c1nccc([O](C)C)c1)=O Chemical compound CC(C)(C)C(CC1)CCC1C(N(CC1)CCN1c1nccc([O](C)C)c1)=O NYZTXWUIESLKRZ-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
- GGFWCDNEFMGGMQ-UHFFFAOYSA-N COc1cc(N2CCNCC2)ncc1 Chemical compound COc1cc(N2CCNCC2)ncc1 GGFWCDNEFMGGMQ-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)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (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 isostructural trans cyclohexane amide structure of class substituted pyridinyl Han alkoxyl, its preparation method and their application in preparation treatment thrombotic disease medicine.Wherein, R is selected from C1‑C3Alkyl, C3‑C5Cycloalkyl.
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 the isostructural trans cyclohexane amide structure of one class substituted pyridinyl Han alkoxyl of therapeutical effect and system thereof
Preparation 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 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 PAR-1 that the invention discloses the isostructural trans cyclohexane amide structure of class substituted pyridinyl Han alkoxyl is short of money
Anti-agent, 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, C3-C5Cycloalkyl.
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 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 as effective 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, route 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, 1.93g (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 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-1, faint yellow solid, ESI-MS, m/z=361 ([M+H]+)。
Embodiment 2-4
With reference to the method for embodiment 1, synthesize the following compounds with formula I.
Embodiment 5 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, 10mMHEPES, 0.35%BSA, 5.5mM Fructus Vitis viniferae
Sugar, pH=7.4) in, and regulate the platelet count to 3 × 105/ μ L with Tyrode.By this for 13mL cell suspension with 866
The 10mM CaCl of μ L2Solution processes, and is drawn in 96 orifice plates with the amount of every hole 120 μ L, has shifted to an earlier date in the hole of 96 orifice plates
Add 15 μ L materials to be tested.At room temperature dark is hatched 30 minutes, add 15 μ L TRAP solution (70-100 μM) conducts
Agonist, vibrates 20 minutes at 37 DEG C in SpectraMax, notes down kinetics, calculate negative control under 650nm
(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.
Compound | The suppression IC of platelet aggregation50(μM) |
Compound I-1 | 1.7 |
Compound I-2 | 3.4 |
Compound I-3 | 3.0 |
Compound I-4 | 4.9 |
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, is selected from:
3. compound described in any one of claim 1-2 and pharmaceutically acceptable salt preparation treatment thrombotic medicine side
The purposes in face.
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CN201410635580.1A CN104356058B (en) | 2014-11-02 | 2014-11-02 | Trans cvclohexvl alkyl amide compound containing alkoxy pyridines and purposes |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998054164A1 (en) * | 1997-05-30 | 1998-12-03 | Takeda Chemical Industries, Ltd. | Sulfonamide derivatives, their production and use |
WO2006057868A1 (en) * | 2004-11-29 | 2006-06-01 | Eli Lilly And Company | Antithrombotic diamides |
CN101010299A (en) * | 2004-06-15 | 2007-08-01 | 布里斯托尔-迈尔斯斯奎布公司 | Six-membered heterocycles useful as serine protease inhibitors |
CN101341124A (en) * | 2005-12-14 | 2009-01-07 | 布里斯托尔-迈尔斯斯奎布公司 | Six-membered heterocycles useful as serine protease inhibitors |
-
2014
- 2014-11-02 CN CN201410635580.1A patent/CN104356058B/en not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998054164A1 (en) * | 1997-05-30 | 1998-12-03 | Takeda Chemical Industries, Ltd. | Sulfonamide derivatives, their production and use |
CN101010299A (en) * | 2004-06-15 | 2007-08-01 | 布里斯托尔-迈尔斯斯奎布公司 | Six-membered heterocycles useful as serine protease inhibitors |
WO2006057868A1 (en) * | 2004-11-29 | 2006-06-01 | Eli Lilly And Company | Antithrombotic diamides |
CN101341124A (en) * | 2005-12-14 | 2009-01-07 | 布里斯托尔-迈尔斯斯奎布公司 | Six-membered heterocycles useful as serine protease inhibitors |
Non-Patent Citations (1)
Title |
---|
Discovery and biological evaluation of adamantly amide 11β-HSD1 inhibitors;Scott P. Webster 等;《Bioorganic & Medicinal Chemistry Letters》;20070225;第17卷(第10期);第2838-2843页 * |
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