CN104387341B - A kind of trans cvclohexvl alkyl amide compound and purposes - Google Patents
A kind of trans cvclohexvl alkyl amide compound and purposes Download PDFInfo
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- CN104387341B CN104387341B CN201410654750.0A CN201410654750A CN104387341B CN 104387341 B CN104387341 B CN 104387341B CN 201410654750 A CN201410654750 A CN 201410654750A CN 104387341 B CN104387341 B CN 104387341B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
Abstract
The present invention relates to the drug world relevant to thrombotic disease.Specifically, the present invention relates to PAR 1 antagonist containing trans cyclohexane amide structure 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
PAR-1 antagonist containing trans cyclohexane amide structure of therapeutical effect a kind of and in preparation treatment thrombotic disease medicine
Application.
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 trans cyclohexane amide structure of a kind of formula (I) structure, it can be used
In the medicine preparing anti-arterial thrombus disease.
Summary of the invention
It is an object of the present invention to provide the compound containing trans cyclohexane amide structure of a kind of formula (I) 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:
The method of preparation formula (I) compound is as follows:
Step is described as follows:
(1) compound II be converted into correspondence acyl chlorides II-C, the reagent of use selected from SOCl2, (COCl) 2, PCl5 and
PCl3。
(2) II-C reacts with compound III in the presence of a base, obtains compound I.
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 the SOCl that 1.84g (10mmol) compound II and 10mL heavily steams2, then exist
The lower temperature rising reflux of stirring 3 hours.
Reactant mixture under reduced pressure steams the SOCl of excess2, the dichloromethane that residue II-C is dried with 20mL dissolves,
Gained mixture stirs under ice-water bath cools down, and slowly drips by 1.62g (10mmol) III and 3.04g (30mmol) triethylamine
It is dissolved in the solution that the dichloromethane that 5mL is dried is made, continues to be stirred at room temperature overnight.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-yellowish 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,
It is centrifuged 20 minutes under 1500g, will be enriched in hematoblastic blood plasma (PRP) and separate and with the 1 μ LPGE1 solution (second of 500 μ g/mL
Alcoholic solution) amount of/mL PRP processes.After at room temperature hatching 5 minutes, it is centrifuged under 1200g 20 minutes to remove
Leukocyte.PRP without leukocyte is transferred to 5mL/ part in the PP pipe of 15mL in batches, and centrifugal under 3600g make blood little
Plate precipitates.Then, drain upper plasma, the pellet platelets deriving from 5mL PRP is suspended in 1mL Tyrode (120mM again
NaCl, 2.6mM KCl, 12mM NaHCO3, 0.39 mM NaH2PO4, 10mM HEPES, 0.35%BSA, 5.5mM glucose, pH
=7.4) in, and the platelet count to 3 × 105/ μ L is regulated with Tyrode.By this for 13mL cell suspension with 866 μ L's
10mM CaCl2Solution processes, and is drawn in 96 orifice plates with the amount of every hole 120 μ L, adds the most in advance in the hole of 96 orifice plates
15 μ L materials to be tested.At room temperature dark is hatched 30 minutes, add 15 μ L TRAP solution (70-100 μM) as exciting
Agent, vibrates 20 minutes at 37 DEG C in SpectraMax, notes down kinetics, calculate negative control (tyrode/ under 650nm
DMSO) and the area under curve of positive control (15 μ L agonist/DMSO), and difference is set to 100%.By compound to be tested
Aspirate with the form of serial dilution thing, be measured in duplicate, the same AUC measuring each material concentration, calculate and compare
The AUC compared suppresses %.IC is calculated according to 4 parametric equations by nonlinear regression analysis by this suppression %50Value.Following table is given
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 (3)
1. there is compound and the pharmaceutically acceptable salt thereof of Formulas I structure,
2. the method for compound described in preparation claim 1,
Specifically comprise the following steps that
(1) compound II is converted into the acyl chlorides II-C of correspondence, and the reagent of use is selected from SOCl2、(COCl)2、PCl5And PCl3。
(2) II-C reacts with compound III in the presence of a base, obtains compound I.
3. compound described in claim 1 and pharmaceutically acceptable salt use in terms of preparation treatment thrombotic medicine
On the way.
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CN201410654750.0A CN104387341B (en) | 2014-11-04 | 2014-11-04 | A kind of trans cvclohexvl alkyl amide compound and purposes |
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CN104387341A CN104387341A (en) | 2015-03-04 |
CN104387341B true CN104387341B (en) | 2016-08-17 |
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Family Cites Families (2)
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ATE334975T1 (en) * | 1997-05-30 | 2006-08-15 | Takeda Pharmaceutical | SULFONAMIDE DERIVATIVES, THEIR PRODUCTION AND USE |
ATE440833T1 (en) * | 2004-11-29 | 2009-09-15 | Lilly Co Eli | ANTITHRBOTIC DIAMIDES |
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