CN107304199A - A kind of new himbacine analogs and its application in medicine - Google Patents
A kind of new himbacine analogs and its application in medicine Download PDFInfo
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- CN107304199A CN107304199A CN201710264421.9A CN201710264421A CN107304199A CN 107304199 A CN107304199 A CN 107304199A CN 201710264421 A CN201710264421 A CN 201710264421A CN 107304199 A CN107304199 A CN 107304199A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The present invention relates to a kind of new himbacine analogs, the compound has formula (II) structure, and the stereoisomer, dynamic isomer, prodrug or pharmaceutically acceptable salt or solvate and the pharmaceutical composition containing them of formula (II) compound, with and application thereof
Description
Technical field
The present invention relates to organic chemistry and field of pharmacology, specifically, the present invention relates to a kind of new himbacine is similar
Thing, the compound has formula (II) structure, and formula (II) compound stereoisomer, dynamic isomer, prodrug or medicine
Acceptable salt or solvate and the pharmaceutical composition containing them on, with and application thereof.
Background technology
Cardiocerebrovasculaevents events include acute coronary syndrome (acute coronary syndrome, ACS), miocardial infarction,
Cerebral thrombus etc., with high incidence and the characteristics of high mortality.The World Health Organization also indicates that ischemic angiocardiopathy and cerebrovascular event is
Cause the primary factor of death.Current China has more than 3,000,000 people and dies from cardiovascular and cerebrovascular disease every year, accounts for whole death tolls
40.3%.The causes for pathological of such disease is due to that aggregation forms thrombus after platelet activation, and then causes lacking for body tissue
Blood, therefore curing thrombus is the major way that current prevention cardiocerebrovasculaevents events occur.
Blood platelet is hematoblastic activation process after sticking, and includes the release of a variety of autocrines and paracrine factor,
These factors include adenosine diphosphate (ADP) (adenosine diphosphate, ADP), fibrin ferment, adrenaline, thromboxane element A2,
They not only play signal amplification and maintenance effect to hematoblastic initial reaction, and make blood platelet in blood circulation gradually shape
Into hemostatic plug.A variety of clotting factor activation that platelet surface is combined promotes conversion of prothrombin to be fibrin ferment, and fibrin ferment can
Promote hematoblastic aggregation fibrinogen can be promoted to be converted into fibrin again, this is the main original for promoting blood coagulation and hemostasis
Cause.Reaction of the blood platelet to fibrin ferment is mediated by platelet surface g protein coupled receptor, i.e. thrombin receptor.Further research
It was found that thrombin receptor can be activated by protease hydrolytic, therefore thrombin receptor is otherwise known as proteinase activated receptors
(Protease Activated Receptors, PARs).There are 4 kinds of PARs hypotypes, be distributed widely in tissue, PAR-1, PAR-
3, PAR-4 can be by thrombin activation, and PAR-2 is then activated by trypsase or trypsinlike enzyme.Human platelet only expresses PAR-1
With two kinds of acceptors of PAR-4, wherein PAR-1 plays topmost effect in the platelet activation of thrombin-mediated.Muroid blood is small
Plate expresses two kinds of acceptors of PAR-1 and PAR-3.
The oral antithrombotic reagent listed at present is played a role by suppressing platelet activation approach.Cycloxygenase presses down
Preparation aspirin can suppress thromboxane element A2 generation.Thiophene pyridines medicine (such as clopidogrel) can be with platelet surface
Adp receptor P2Y12 produce Irreversible binding so that suppress ADP platelet activation effect.ADP and thromboxane element A2 cause
Platelet activation approach be all final steps for routine pathology thrombosis and hemostasis, thus use in conjunction epoxidation
Enzyme inhibitor and thiophene pyridines medicine inevitably lead to the upper of hemorrhage complication risk while antithrombotic effect is played
Rise.Although therefore Antiplatelet therapy is clinically achieving preferable effect at present, the bleeding risk that it is brought is still
Merit attention.
The platelet activation approach mediated by PAR-1 is mainly formed with effect to pathologic thrombus.PAR-1 acceptor inhibitors
The platelet activation of thrombin-mediated can be blocked without influenceing the fibrinogen cracking of thrombin-mediated, while PAR-1 acceptors
Inhibitor nor affects on the correlation factor for participating in platelet adhesion reaction, activation or aggregation approach, such as collagen, vWF, ADP and rush blood coagulation
Element is (referring to Coughlin SR.;J Thromb Haemost.,2005,3:1800-1814), thus PAR-1 acceptor inhibitors both
There is antithrombotic to be possible without increasing bleeding risk again, be preferable antiplatelet drug.In addition, thrombin receptor is short of money
Anti-agent can also increase anti thrombotic action with the drug combination such as aspirin, clopidogrel.Thrombin receptor antagonist also has uncommon
Anti arteriosclerosis and the new drug of anticancer are developed into prestige.
Since being found from thrombin receptor, many drugmakers are devoted to the new drug development using thrombin receptor as target spot
Research.A series of patent application of thrombin receptor antagonists is had been disclosed at present, and such as WO03089428 discloses class happiness bar
Pungent derivative;WO2002085855 discloses a kind of 2- lminopyrrolidines analog derivative.Merck companies exploitation fibrin ferment by
Body antagonist SCH530348 shows that SCH530348 significantly reduces the hearts such as miocardial infarction or cerebral thrombus in III clinical trial phase
The incidence of disease of vascular diseases, but simultaneously it has also been found that having bleeding adverse reaction, especially apoplexy, TIA and cerebral hemorrhage
Patient, the increase of brainpan internal haemorrhage probability, this causes the applicable crowd of current thrombin receptor antagonist to greatly reduce.Research and develop bleeding
Side reaction is less, and the more excellent new thrombin receptor antagonist of curative effect still has very big challenge.
Present invention design is with the compound shown in logical formula (II), and the compounds of this invention is compared with specifically disclosed in technology
Compound has a larger architectural difference, and shows excellent effect and effect.
The content of the invention
In order in place of overcoming the deficiencies in the prior art, it is an object of the invention to provide with new shown in formula (II) structure
Himbacine analogs, and their stereoisomer, dynamic isomer or pharmaceutically acceptable salt or solvate, or
Metabolite and metabolic precursor thereof or prodrug,
Compound or its stereoisomer of the one kind with formula (II) structure, dynamic isomer, prodrug can pharmaceutically connect
The salt or solvate received:
Wherein:
R1Selected from heterocyclic radical, aryl or heteroaryl, wherein described heterocyclic radical, aryl or heteroaryl can be further optional
Halogen, hydroxyl, cyano group, nitro, amido ,-NR are selected from by one or more3R4, alkoxy, alkyl, cycloalkyl, heterocyclic radical, virtue
Base, heteroaryl ,-C (O) OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4Substituent replaced;It is wherein described
Alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl can further optionally by it is one or more be selected from halogen, hydroxyl
Base, cyano group, nitro, amido ,-NR3R4, alkoxy, alkyl, cycloalkyl, aryl, the substituent of heteroaryl replaced;
R2Selected from-C (O) OR3、-CN、-C(O)NR3R4, heterocyclic radical, aryl or heteroaryl, wherein described heterocyclic radical, virtue
Base or heteroaryl further optionally can be selected from halogen, hydroxyl, cyano group, nitro, amido ,-NR by one or more3R4, alcoxyl
Base, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)
NR3R4Substituent replaced;Wherein described alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl can be further
Optionally halogen, hydroxyl, cyano group, nitro, amido ,-NR are selected from by one or more3R4, it is alkoxy, alkyl, cycloalkyl, aryl, miscellaneous
The substituent of aryl is replaced;
X is selected from CH or N;
N is selected from 0,1,2 or 3;
R3And R4Hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described is miscellaneous
Ring group, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, amido, alkoxy, alkane by one or more
Base or the substituent of cycloalkyl are replaced.
It is preferred that, the compound or its stereoisomer, dynamic isomer, prodrug or pharmacy of formula (II) structure of the invention
Upper acceptable salt or solvate:
Wherein,
R1Selected from heterocyclic radical, aryl or heteroaryl, wherein described heterocyclic radical, aryl or heteroaryl can be further optional
Halogen, hydroxyl, cyano group, amido ,-NR are selected from by one or more3R4, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl
Base ,-C (O) OR3、-NHC(O)R3、-C(O)NR3R4Substituent replaced;It is wherein described alkoxy, alkyl, cycloalkyl, miscellaneous
Ring group, aryl or heteroaryl further optionally can be selected from halogen, hydroxyl, cyano group, amido ,-NR by one or more3R4, alcoxyl
Base, alkyl, the substituent of cycloalkyl are replaced;
R2Selected from-C (O) OR3、-CN、-C(O)NR3R4Or heteroaryl, wherein described heteroaryl can be further optional
Halogen, hydroxyl, cyano group, amido ,-NR are selected from by one or more3R4, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl
Base ,-C (O) OR3、-NHC(O)R3、-C(O)NR3R4Substituent replaced;It is wherein described alkoxy, alkyl, cycloalkyl, miscellaneous
Ring group, aryl or heteroaryl further optionally can be selected from halogen, hydroxyl, cyano group, amido ,-NR by one or more3R4, alcoxyl
Base, alkyl, the substituent of cycloalkyl are replaced;
X is selected from CH or N;
N is selected from 0,1 or 2;
R3And R4Hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described is miscellaneous
Ring group, aryl or heteroaryl further optionally can be selected from halogen, hydroxyl, cyano group, amido, alkoxy, alkane by one or more
Base or the substituent of cycloalkyl are replaced.
It is preferred that, this such as the compound or its stereoisomer of formula (III) structure, dynamic isomer, prodrug or pharmaceutically may be used
The salt or solvate of receiving:
Wherein,
R1Selected from heterocyclic radical, aryl or heteroaryl, wherein described heterocyclic radical, aryl or heteroaryl can be further optional
Halogen, hydroxyl, cyano group, amido ,-NR are selected from by one or more3R4, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl
Base ,-C (O) OR3、-NHC(O)R3、-C(O)NR3R4Substituent replaced;It is wherein described alkoxy, alkyl, cycloalkyl, miscellaneous
Ring group, aryl or heteroaryl further optionally can be selected from halogen, hydroxyl, cyano group, amido ,-NR by one or more3R4, alcoxyl
Base, alkyl, the substituent of cycloalkyl are replaced;
R2Selected from-C (O) OR3、-CN、-C(O)NR3R4Or heteroaryl, wherein described heteroaryl can be further optional
Halogen, hydroxyl, cyano group, amido ,-NR are selected from by one or more3R4, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl
Base ,-C (O) OR3、-NHC(O)R3、-C(O)NR3R4Substituent replaced;It is wherein described alkoxy, alkyl, cycloalkyl, miscellaneous
Ring group, aryl or heteroaryl further optionally can be selected from halogen, hydroxyl, cyano group, amido ,-NR by one or more3R4, alcoxyl
Base, alkyl, the substituent of cycloalkyl are replaced;
R3And R4Hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described is miscellaneous
Ring group, aryl or heteroaryl further optionally can be selected from halogen, hydroxyl, cyano group, amido, alkoxy, alkane by one or more
Base or the substituent of cycloalkyl are replaced.
Most preferably, typical compound of the invention includes, but are not limited to:
The present invention relates to any one compound in formula (II) or its stereoisomer, dynamic isomer, prodrug in pharmacy
Upper acceptable salt or solvate, wherein pharmaceutically acceptable salt are the compound and inorganic acid/organic acid or inorganic
The conventional non-toxic salts of alkali/organic base formation, these salt can be mono-salt, disalt, three salt or salty, as contained by the compound
Can be determined into salt functional group.If wherein described formula (II) compound contains basic functionality, can with sulfuric acid, hydrochloric acid,
Hydrobromic acid, phosphoric acid, tartaric acid, fumaric acid, maleic acid, citric acid, acetic acid, formic acid, methanesulfonic acid, p-methyl benzenesulfonic acid, oxalic acid or amber
Amber acid forms acid-addition salts, and these salt can be according to conventional chemical processes from the compounds of this invention and phase comprising basic functionality
Answer inorganic acid/organic acid reaction synthesis;If formula (II) compound contains acidic functionality, it can be formed with alkaline reagent
Stable alkali metal salt, alkali salt or optionally substituted ammonium salt, the alkaline reagent is such as hydroxide, carbonate,
Bicarbonate, alkoxide and ammonia or organic base, such as Trimethylamine, triethylamine, monoethanolamine, diethanol amine, three ethanol
Amine, tromethamine or other basic amino acids, such as lysine, ornithine or arginine;These salt can be according to routinizing
Method is synthesized from the compounds of this invention comprising acidic functionality and corresponding inorganic base/organic base reaction.
The invention further relates to the compound pharmaceutically acceptable solvate, including Conventional solvents compound, for example
Compound of the present invention solvate formed by solvent is present in preparation process, by the presence shape of water or ethanol
Into solvate can be used as non-limiting examples.
Another aspect of the present invention is related to the isomers of any one compound in the formula (II) structure, formula (II) structure
There are one or more carbon-carbon double bonds in the compound, it is understood that there may be cis-trans-isomer, without present invention bag under specified otherwise
Mixture containing all cis-trans-isomer or different proportion isomers compositions that may be present;Change described in same up-to-date style (II) structure
Also there is under one or more chiral centres, no specified otherwise the present invention in compound comprising all that may be present in theory to disappear
Revolve body, racemic mixture, enantiomter, diastereoisomer and non-corresponding isomer mixture.Heretofore described
Chemical structural formula, chemical name include all isomers that may be present in theory of the compound.
Formula if (II) compound exist with the form of mixtures of diastereoisomer or enantiomter or
Obtained in selected synthesis with its form of mixtures, then can be separated into optical voidness solid as follows different for formula (II) described compound
Structure body:Carry out chromatographic isolation on the carrier mass of player's property in office, or if racemic compound can forming salt, then also can be with
Fractional crystallization is carried out as the diastereomeric salt of optical active alkali or the optically active acid formation of auxiliary agent.For diastereomeric
The example of the proper chiral stationary phase of isomers TLC separation or column chromatography is that modified silica gel carrier (turns into Pirkle
Phase) and high-molecular-weight hydrocarbons such as tri acetyl cellulose.In order to outer containing acidic-group in separate type (II) described compound
Raceme, with optical active alkali such as (-)-nicotine, (+)-and (-)-phenyl ethyl amine, quinine alkali, 1B, L-arginine
With diastereomeric salt of the D-Arg formation with different solubilities, the less component of solubility is come to divide in solid form
Obtained from, the diastereomeric salt that pure enantiomter is obtained by above method.Contain in formula (II) described compound
The racemic modification of basic group such as amino can be as stated above with optically active acid such as (+)-camphor -10- sulfonic acid, D- and L-
Tartaric acid, D- and Pfansteihl, D- and L- mandelic acids change into pure enantiomter.
Another aspect of the present invention be related to formula (II) compound or its stereoisomer, dynamic isomer, prodrug or
There may be at least one in the isotope substituent of pharmaceutically acceptable salt or solvate, one compound of any of which
Hydrogen atom is replaced by D-atom or at least one carbon atom or fluorine atom are replaced by corresponding isotope.
Another aspect of the present invention is related to a kind of pharmaceutical composition, and it contains in formula (II) any one compound or it is vertical
Body isomers, dynamic isomer, prodrug or pharmaceutically acceptable salt or solvate and pharmaceutically useful carrier.
Another aspect of the present invention is related to any one compound or its stereoisomer, tautomerism described in formula (II)
Body, prodrug or pharmaceutically acceptable salt or solvate, or pharmaceutical composition are preparing the medicine of thrombin receptor antagonist
In purposes.
Another aspect of the present invention is related to any one compound or its stereoisomer, tautomerism described in formula (II)
Body, prodrug or pharmaceutically acceptable salt or solvate, or pharmaceutical composition are preparing the medicine of thrombin receptor antagonist
In purposes, wherein thrombin receptor antagonist is PAR1 receptor antagonists.
Another aspect of the present invention is related to any one compound or its stereoisomer, tautomerism described in formula (II)
Body, prodrug or pharmaceutically acceptable salt or solvate, or pharmaceutical composition are preparing the medicine of platelet aggregation inhibitor
In purposes.
Another aspect of the present invention is related to any one compound or its stereoisomer, tautomerism described in formula (II)
Body, prodrug or pharmaceutically acceptable salt or solvate, or pharmaceutical composition prepare treatment and/or prevention with fibrin ferment by
Body has the purposes in the medicine of related disorders, wherein it is described have with thrombin receptor related disorders be selected from artery and Venous Thrombosis,
Acute coronary syndrome, ISR, stable angina cordis, arrhythmia, miocardial infarction, hypertension, heart failure, apoplexy,
PUD D, gastrointestinal disease, rheumatism, asthma, chronic hepatic fibrosis, tumour and the skin diseases such as inflammatory disease, pulmonary embolism disease.
Another aspect of the present invention is related to any one compound or its stereoisomer, tautomerism described in formula (II)
Body, prodrug or pharmaceutically acceptable salt or solvate, or pharmaceutical composition and the product of another cardiovascular drugs,
Simultaneously or treating cardiovascular disease is respectively used to as combination product, wherein described another kind of cardiovascular drugs are to be selected from
The anti-platelet aggregation medicinals such as aspirin, clopidogrel, Ticlopidine, Abciximab, tirofiban or eptifibatide.
Present invention additionally comprises containing the compounds of this invention or its stereoisomer, dynamic isomer, prodrug or pharmaceutically may be used
The salt of receiving or the pharmaceutical composition of solvate.
The pharmaceutical composition of the present invention, can be any medicament forms taken:Such as tablet, sugar coated tablet, film-coating
Tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, mouth containing agent, granule, electuary, pill, powder,
Paste, sublimed preparation, supensoid agent, pulvis, solution, injection, suppository, ointment, emplastrum, creme, spray, drops or patch
Agent.
The pharmaceutical dosage forms of the pharmaceutical composition, preferably unit dose of the present invention.
The pharmaceutical composition of the present invention, when medicament is made, the medicament of unit dose can the pharmaceutical activity containing the present invention
Material 0.1-1000mg, remaining is pharmaceutically acceptable carrier.Pharmaceutically acceptable carrier can be preparation by weight
The 0.01-99.99% of gross weight.
The composition of the present invention determines usage and dosage according to the situation of patient when in use, such as 1-3 times on the one.1-10
Piece etc..
It is preferred that, composition of the invention is oral formulations or injection.
Wherein, the oral formulations are in capsule, tablet, dripping pill, granule, condensed pill, oral liquid and mixture
It is a kind of.
Wherein, the one kind of the injection in parenteral solution, freeze drying powder injection and liquid drugs injection.
The pharmaceutical composition of the present invention, its preparation being administered orally can contain conventional excipient, such as adhesive, filling
Agent, diluent, tablet agent, lubricant, disintegrant, colouring agent, flavor enhancement or wetting agent, can be coated to tablet if necessary.
Applicable filler includes cellulose, mannitol, lactose or other similar fillers.Suitable disintegrant bag
Include starch, polyvinylpyrrolidone or starch derivatives, preferably sodium starch glycollate.Suitable lubricant is magnesium stearate.
Suitable wetting agent is lauryl sodium sulfate.
The pharmaceutical composition of the present invention can be filled by mixing, and the conventional method such as tabletting prepares solid oral composition.
Carrying out mixing repeatedly can be such that active material is distributed in entirely using in the composition of a large amount of fillers.
The form of oral liquid can be aqueous or oily suspensions, solution, emulsion, syrup or elixir, also may be used
To be a kind of dry products that can be compounded before use with water or other suitable carriers.This liquid preparation can contain routine
Additive, such as suspending agent, such as sorbierite, syrup, methylcellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose,
Aluminium stearate gel or hydrogenated edible fats, emulsifying agent, such as lecithin, anhydro sorbitol monooleate or Arabic gum;It is non-
Aqueous carrier (they can include edible oil), such as apricot kernel oil, fractionated coconut oil, the oily ester of such as glyceride, propane diols
Or ethanol;Preservative, such as para hydroxybenzene methyl esters, propylparaben or sorbic acid, and if desired, can be containing normal
The flavouring agent or colouring agent of rule.
For injection, the fluid unit dosage form of preparation contains the active material and sterile carrier of the present invention.According to carrier
And concentration, this compound can be suspended or be dissolved.The preparation of solution is dissolved in a kind of load typically by by active material
In body, sterilization is filtered before a kind of suitable bottle or ampoule is loaded into, is then sealed.For example a kind of local anaesthesia of auxiliary material
Agent, preservative and buffer can also be dissolved in this carrier., can be after bottle be loaded by this in order to improve its stability
Composition frost is planted, and under vacuo removes water.
The pharmaceutical composition of the present invention, suitable pharmaceutically acceptable load is optionally added when being prepared into medicament
Body, the pharmaceutically acceptable carrier is selected from following one or more:Mannitol, sorbierite, sodium pyrosulfite, bisulfite
Sodium, sodium thiosulfate, cysteine hydrochloride, TGA, methionine, injection Vitamin B_6 DTA disodiums, Ethylenediaminetetraacetic Acid Calcium Salt, monoacidic base gold
Carbonate, acetate, phosphate or its aqueous solution of category, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium chloride, potassium chloride,
Sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon spread out
Biology, cellulose and its derivates, alginates, gelatin, polyvinylpyrrolidone, glycerine, POLYSORBATE 80, agar, calcium carbonate, carbonic acid
Hydrogen calcium, surfactant, polyethylene glycol, cyclodextrin, beta-schardinger dextrin, phospholipid material, kaolin, talcum powder, calcium stearate,
Magnesium stearate etc..
The pharmaceutical dosage form of the present invention is not exclusively confined to this, and it can be prepared into more formulations, such as dripping pill, sustained release preparation
Etc. any medicament forms taken.
The detailed description of invention
Unless stated to the contrary, the term used in the specification and in the claims has following implications.
" halogen " refers to fluorine, chlorine, bromine, iodine.
" alkyl " refers to the aliphatic hydrocarbon groups of saturation, includes the straight chain and branched group of 1 to 20 carbon atom.Preferably comprise
The alkyl of 1 to 12 carbon atom, non-limiting example include methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group,
The tert-butyl group, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl propyls, 2,2- dimethyl propyls, 1- ethyl propyls,
2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls propyl group, 1,1,2_ thmethylpropyl, 1,1- dimethyl butyrates
Base, 1,2- dimethylbutyls, 2,2_ dimethylbutyls, 1,3- dimethylbutyls, 2- ethyl-butyls, 2- methyl amyls, 3- methyl
Amyl group, 4- methyl amyls, 2,3_ dimethylbutyls, n-heptyl, 2- methylhexyls, 3- methylhexyls, 4- methylhexyls, 5- methyl
Hexyl, 2,3- dimethyl amyl groups, 2,4_ dimethyl amyl groups, 2,2- dimethyl amyl groups, 3,3- dimethyl amyl groups, 2- ethyl pentyl groups,
3- ethyl pentyl groups, n-octyl, 2,3_ dimethylhexanyls, 2,4_ dimethylhexanyls, 2,5_ dimethylhexanyls, 2,2_ dimethyl oneself
Base, 3,3_ dimethylhexanyls, 4,4_ dimethylhexanyls, 2- ethylhexyls, 3- ethylhexyls, 4- ethylhexyls, 2- methyl -2- second
Base amyl group, 2- methyl -3- ethyl pentyl groups, n-nonyl, 2- methyl -2- ethylhexyls, 2- methyl -3- ethylhexyls, 2,2- diethyls
Base amyl group, positive decyl, 3,3- diethylhexyls, 2,2- diethylhexyls, and its various branched chain isomers etc..More preferably contain
There is a low alkyl group of 1 to 6 carbon atom, non-limiting example includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, different
Butyl, the tert-butyl group, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl propyls, 2,2_ dimethyl propyls, 1- ethyls
Propyl group, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls propyl group, 1,1,2- thmethylpropyl, 1,1- diformazans
Base butyl, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- dimethylbutyls, 2- ethyl-butyls, 2- methyl amyls, 3-
Methyl amyl, 4- methyl amyls, 2,3- dimethylbutyls etc..Alkyl can be substituted or unsubstituted, when substituted, take
Can be substituted for base on any workable tie point, preferably one or more following groups, independently selected from halogen,
Hydroxyl, cyano group, nitro, amido ,-NR3R4, alkoxy, alkyl, cycloalkyl, aryl, heteroaryl.
" cycloalkyl " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and it includes 3 to 20 carbon atoms,
3 to 12 carbon atoms are preferably included, more preferably cycloalkyl ring includes 3 to 10 carbon atoms.The non-limiting reality of monocyclic cycloalkyl
Apply example and include cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptyl
Trialkenyl, cyclooctyl etc..Polycyclic naphthene base includes the cycloalkyl of loop coil, condensed ring and bridged ring.
" spiro cycloalkyl group " refers to 5 to 20 yuan, it is monocyclic between share the polycyclic moiety of a carbon atom (title spiro-atom), these can
With containing one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably
For 7 to 10 yuan.According between ring and ring share spiro-atom number by spiro cycloalkyl group be divided into single spiro cycloalkyl group, double spiro cycloalkyl groups or
Many spiro cycloalkyl groups, are preferably single spiro cycloalkyl group and double spiro cycloalkyl groups.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5
Member or 5 yuan/6 yuan single spiro cycloalkyl groups.
" bridge ring alkyl " refers to 5 to 20 yuan, and any two ring shares many ring groups of full carbon of two carbon atoms being not directly connected
Group, these can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14
Member, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic bridge ring alkyl can be divided into according to the number of composition ring, preferably
For bicyclic, three rings or Fourth Ring, more preferably bicyclic or three rings.
The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocycloalkyl ring, wherein being connected to precursor structure
Ring together is cycloalkyl, and non-limiting example includes indanyl, tetralyl, benzocyclohepta alkyl etc..Cycloalkyl can be with
It is optionally substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, independently selected from halogen
Element, hydroxyl, cyano group, nitro, amido ,-NR3R4, alkoxy, alkyl, cycloalkyl, aryl, heteroaryl.
" heterocyclic radical " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and it includes 3 to 20 annular atoms,
Wherein one or more annular atoms are selected from N, O or S (O)mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom is C.It is excellent
Choosing includes 3 to 12 annular atoms, wherein 1~4 is hetero atom, more preferably cycloalkyl ring includes 3 to 10 annular atoms.It is monocyclic miscellaneous
The non-limiting example of ring group includes pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base etc.;
Multiring heterocyclic includes the heterocyclic radical of loop coil, condensed ring and bridged ring.
" spiro heterocyclic radical " refers to 5 to 20 yuan, it is monocyclic between share the polycyclic heterocyclic group of an atom (title spiro-atom), wherein
One or more annular atoms are selected from N, O or S (O)mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom is C.These can
With containing one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably
For 7 to 10 yuan.According between ring and ring share spiro-atom number by spiro heterocyclic radical be divided into single spiro heterocyclic radical, double spiro heterocyclic radicals or
Many spiro heterocyclic radicals, are preferably single spiro heterocyclic radical and double spiro heterocyclic radicals.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5
Member or 5 yuan/6 yuan single spiro cycloalkyl groups.
" condensed hetero ring base " refers to each ring in 5 to 20 yuan, system and shared a pair of the atoms adjoined of other rings in system
Polycyclic heterocyclic group, one or more rings can contain one or more double bonds, but neither one ring has the π of total conjugated
Electronic system, wherein one or more annular atoms are selected from N, O or S (O)mThe hetero atom of (wherein m is integer 0 to 2), remaining ring is former
Son is C.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to composition ring number can be divided into bicyclic, three rings, Fourth Ring or
Polycyclic fused heterocycloalkyl, preferably bicyclic or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic condensed hetero ring bases.
" bridge heterocyclic radical " refers to 5 to 14 yuan, and any two ring shares the polycyclic heterocyclic group of two atoms being not directly connected,
These can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated, wherein one or more
Annular atom is selected from N, O or S (O)mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom is C.Preferably 6 to 14 yuan, more
Preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic bridge heterocyclic radical can be divided into according to the number of composition ring, are preferably double
Ring, three rings or Fourth Ring, more preferably bicyclic or three rings.
The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein being connected to one with precursor structure
The ring risen is heterocyclic radical;Heterocyclic radical can be it is optionally substituted or unsubstituted, when substituted, substituent be preferably one or
Multiple following groups, independently selected from halogen, hydroxyl, cyano group, nitro, amido ,-NR3R4, alkoxy, alkyl, cycloalkyl, virtue
Base, heteroaryl.
" aryl " refers to that 6 to 14 yuan of full carbon are monocyclic or fused polycycle (rings for namely sharing adjacent carbon atoms pair) group, tool
There are polycyclic (i.e. its ring for carrying phase adjacency pair carbon atom) group, such as preferably 6 to 10 yuan, phenyl of the pi-electron system of conjugation
And naphthyl.The aryl rings can be condensed on heteroaryl, heterocyclic radical or cycloalkyl ring, wherein being linked together with precursor structure
Ring be aryl rings;Aryl can be substituted or unsubstituted, and when substituted, substituent is preferably one or more following
Group, independently selected from halogen, hydroxyl, cyano group, nitro, amido ,-NR3R4, alkoxy, alkyl, cycloalkyl, aryl, heteroaryl.
" heteroaryl " refers to comprising 1 to 4 hetero atom, and the heteroaromatic system of 5 to 14 annular atoms, wherein hetero atom include
Oxygen, sulphur and nitrogen.Preferably 6 to 10 yuan, be more preferably 5 yuan or 6 yuan, such as furyl, thienyl, pyridine radicals, pyrrole radicals, N-
Alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical etc..The heteroaryl ring can condense in aryl, heterocyclic radical or
On cycloalkyl ring, wherein being heteroaryl ring with the ring that precursor structure links together;Heteroaryl can be optionally substituted or not
Substitution, when substituted, substituent is preferably one or more following groups, independently selected from halogen, hydroxyl, cyano group, nitre
Base, amido ,-NR3R4, alkoxy, alkyl, cycloalkyl, aryl, heteroaryl.
" alkoxy " refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), and wherein alkyl is as defined above.Non- limit
Property embodiment processed includes methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy
Deng.Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituent is preferably one or more following bases
Group, independently selected from for halogen, hydroxyl, cyano group, nitro, amido ,-NR3R4, alkoxy, alkyl, cycloalkyl, aryl, heteroaryl.
" optional " or " optionally " mean ground described later event or environment can with but necessarily occur, the explanation bag
Include the event or environment generation or not spot occasion.For example, " optionally by alkyl-substituted heterocyclic group " means that alkyl can
With but necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted feelings
Shape.
" pharmaceutical composition " represent containing one or more compounds described herein or its physiologically/pharmaceutically useful salt or
Pro-drug and the mixture of other chemical constituents, and other components such as physiology/pharmaceutically useful carrier and excipient.Medicine
The purpose of compositions is to promote the administration to organism, the absorption beneficial to active component and then performance bioactivity.
Embodiment
Further illustrated below by specific embodiment in the present invention, following embodiments and give representative compound
Synthesis and dependency structure appraising datum, it is used to illustrate rather than limitation of the present invention, according to the essence of the present invention
The scope of protection of present invention is belonged to the simple modifications that the present invention is carried out.
Embodiment 1:N- [(1R, 3aR, 4aR, 8aR, 9S, 9aS) -9- [(1E) -2- [5- (3- fluorobenzene) -2- pyridine radicals]-second
Alkenyl] ten dihydro -1- methyl -3- oxos naphtho- [2,3-c] furans -6- bases] -9a- amion acetic acids (II-1)
N-[(1R,3aR,4aR,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)-2-pyridinyl]
ethenyl]d odecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-9a-yl]amino acetic
acid(II-1)
The first step:
1f (10.7g, 33mmol) is dissolved in 100mL THF, nitrogen protection is cooled to 0 DEG C, n-BuLi is added dropwise
(13.3mL, 2.5M, 33mmol), control temperature continues to react 1.5h at 0 DEG C or so;7a is added dropwise【Synthetic method is shown in
J.Med.Chem.2005,48,5884-5887】The 40mL THF solutions of (3.9g, 16.5mmol), temperature control at -5 DEG C, after
Continuous reaction 1h;100mL saturated ammonium chloride solutions are added into system reaction is quenched, 100mL ethyl acetate is extracted 1 time, saturation food
Salt is washed 1 time, and (EA is purified through column chromatography after drying concentration:PE=1:5) compound 7b white solid 4.6g (yields are obtained
69.6%).
Second step:
7b (1g, 2.47mmol) is dissolved in the anhydrous THF of 10mL, the lower system of nitrogen protection is cooled to -78 DEG C, starts to be added dropwise
LHMDS (3.8mL, 4.93mmol), is warmed to room temperature reaction 30min naturally;System is cooled to -78 DEG C, be added dropwise DBAD (1.1g,
Reaction 1.5h is warmed to room temperature after THF solution 4.93mmol), completion of dropwise addition;System pours into 300mL saturated ammonium chloride solution
In, point liquid, aqueous phase is extracted with 30mL ethyl acetate, through saturated common salt water washing, is dried solids after concentration and is dissolved in 50mL ethanol,
Raney's nickel (0.1g) is added, hydrogen is replaced 3 times, 0.1MPa hydrogen reaction 10h, filtering and concentrating obtains 350mg light yellow liquids 7c (receipts
Rate 33.9%).
3rd step:
At room temperature, N2In protection, the MeOH that TEA is added to 7c (100mg, 0.23mmol), 15min is reacted at room temperature;To
Glyoxalic acid solution (35mg, 0.23mmol) is added in system, 30min is reacted at room temperature;NaBH is added into system3CN (15mg,
0.23mmol), 1h is reacted at room temperature;Add a small amount of water-methanol into system to be quenched, directly concentration is spin-dried for, prepared by thin-layer chromatography
(MeCN:H2O=5:1), it is concentrated to give faint yellow solid compound ii -1 (40mg, yield 26%).
1H NMR(DMSO,400MHz):δ 8.74 (1H, s), 8.01 (1H, d, J=8.0Hz), 7.53-7.51 (6H, m),
7.41 (1H, d, J=10.0Hz), 7.13 (1H, s), 6.63 (2H, d, J=3.6Hz), 4.79 (1H, s), 3.55-3.31 (2H,
M), 2.62 (1H, d, J=5.2Hz), 2.25 (1H, d, J=3.2Hz), 1.78-1.31 (14H, m), 1.01 (1H, m), 0.95
(1H,m);
ESI-MS:479.2[M+H]+
Embodiment 2:N- [(1R, 3aR, 4aR, 8aR, 9S, 9aS) -9- [(1E) -2- [5- (3- fluorobenzene) -2- pyridine radicals]-second
Alkenyl] ten dihydro -1- methyl -3- oxos naphtho- [2,3-c] furans -6- bases] -9a- ethyl aminoacetates (II -2)
N-[(1R,3aR,4aR,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)-2-pyridinyl]
ethenyl]d odecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-9a-yl]amino acetic
acid ethyl ester(II-2)
At room temperature, by 7c (150mg, 0.35mmol), bromoacetate (187mg, 1.07mmol), DIPEA (276mg,
2.14mmol) it is dissolved in 10mL acetonitriles, N2Protect lower 85 DEG C of reactions 10h;System is cooled to room temperature, adds 30mL water, acetic acid second
Ester 50mL is extracted, and organic phase is dried after concentration through thin-layer chromatography (DCM:EA=4:1) compound ii -2 (44mg, yield are purified to obtain
24.8%).
1H NMR(DMSO,400MHz):δ 8.77 (1H, s), 7.83 (1H, d, J=2.0Hz), 7.49 (1H, m), 7.37
(1H,s),7.28(2H,m),7.09(1H,s),6.63-6.57(2H,m),4.67(1H,m),4.23(2H,m),3.59-3.40
(2H,m),2.67(1H,m),2.16(2H,m),1.74-1.09(18H,m),0.92(1H,m),0.86(1H,m);
ESI-MS:507.6[M+H]+
Embodiment 3:N- [(1R, 3aR, 4aR, 8aR, 9S, 9aS) -9- [(1E) -2- [5- (3- fluorobenzene) -2- pyridine radicals]-second
Alkenyl] ten dihydro -1- methyl -3- oxos naphtho- [2,3-c] furans -6- bases] -9a- aminoacetonitriles (II-3)
N-[(1R,3aR,4aR,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorophenyl)-2-pyridinyl]
ethenyl]d odecahydro-1-methyl-3-oxonaphtho[2,3-c]furan-9a-yl]amino
acetonitrile(II-3)
At room temperature, by 7c (120mg, 0.29mmol), bromoacetonitrile (103mg, 0.86mmol), DIPEA (110mg,
0.86mmol) it is dissolved in 10mL acetonitriles, N2Protect lower 85 DEG C of reactions 10h;System is cooled to room temperature, adds 30mL water, acetic acid second
Ester 50mL is extracted, and organic phase is dried after concentration through thin-layer chromatography (DCM:EA=4:1) compound ii -3 (30mg, yield are purified to obtain
23%).
1H NMR(DMSO,400MHz):δ 8.77 (1H, s), 7.82 (1H, d, J=2.0Hz), 7.44 (1H, d, J=
6.0Hz), 7.41 (1H, s), 7.37 (4H, s), 7.09 (1H, d, J=6.8Hz), 6.65 (2H, s), 4.74 (1H, m), 3.89
(1H, d, J=17.6Hz), 3.52 (1H, d, J=17.6Hz), 2.56 (1H, m), 2.33 (1H, m), 1.85-1.21 (18H, m),
0.91(1H,m),0.88(1H,m);
ESI-MS:460.25[M+H]+
Biological test embodiment:Calcium ion transport Inhibition test
Model described below shows that compound of the present invention is PAR-1 acceptor inhibitors.In various cell types,
Activating PAR-1 acceptors triggering intracellular signaling pathway by selective PAR-1 activators causes endoplasmic reticulum to discharge calcium ion.In table
In intelligent's class PAR1 KNRK cell lines, determine what is activated by SFLLR by fluorescent technique using calcium ion selective probe
To the calcium release in acceptor.The emissive porwer of fluorescence is directly proportional to the activity and concentration of PAR-1 antagonists.This method can be determined
Influence of the compounds of this invention to the PAR-1 calcium ion transports mediated.
First, experiment material:
Reagent:HBSS buffer solutions, HEPES, probenecid, BSA, Calcium 4dye are purchased from Invitrogen.
TFLLR-NH2, the reagent such as SCH-79797 provides by French SEREP companies.
Cell line:Stable expression mankind PAR1 KNRK cell lines.
Fluorescence microscope:CellLux(PerkinElmer).
Compound ii -1~II -3:There is provided by research institute of Tasly Pharmaceutical Group Co., Ltd..
Buffer solution is prepared with stoste:
Assay buffer:1 × HBSS buffer solutions, are configured to HEPES containing 20mM, 2.5mM probenecid, and 0.1%
BSA, PH=7.4 (probenecid and BSA needs Fresh) buffer solution;
Loading buffer:1 × HBSS buffer solutions, are configured to HEPES containing 20mM, 2.5mM probenecid,
0.1%BSA, PH=7.4 (probenecid and BSA needs Fresh), 2 μM of calcium 4dye buffer solution;
Compound stock solution (5 × CPD):100%DMSO dissolved compounds are used first, and it is 10mM to make final compound concentration.It is real
When testing, above-mentioned stoste is configured to 5 times of strength solutions with assay buffer standby;
6×TFLLR-NH2:HaTRAP is diluted to final concentration of 30uM with assay buffer standby.
React final volume:6 × TFLLR-NH of 20uL loading buffer, 5uL 5 × CPD, 5uL2(haTRAP, eventually
Concentration is 5uM).
2nd, experimental procedure:
1st, sterile 384 orifice plate, 37 DEG C of placement 15-30min are handled with 1 times of Matrigel in advance;
2nd, 2 × 10 will be added in every hole of above-mentioned sterile 384 orifice plate handled well4Individual stable expression mankind PAR1 KNRK
Cultivated 24 hours in cell, cell culture incubator;
3rd, the cell culture fluid in 384 orifice plates is removed, adds 20uL 4dye containing Calcium loading buffer;
4th, the lucifuge culture 60min in incubator;
5 and then it is further cultured for adding 5uL 5 times of compound stock solutions in hole that (DMSO final concentration of 1%) continues to cultivate
15min, then adds 6 times of TFLLR-NH of 5uL2, fluorescence intensity is recorded under fluorescence microscope 100 seconds.
6th, inhibitor activity is expressed as fluorescence intensity of the inhibitor under various concentrations and accounts for blank control in experimental result
HaTRAP excites the percentage of fluorescence intensity.Test compound is calculated PAR-1 inhibiting rate as follows:IR=(FNC-
FTC)/FNC%
FNC:The fluorescence intensity in negative control group hole
FTC:The fluorescence intensity in test compound hole
Under 10 μM of concentration, Ca2+ oscillations antagonism>60%, derivative of the invention is accredited as PAR-1 receptor antagonists
Agent.
7th, the half-inhibition concentration IC50 of test compound can be calculated by the inhibiting rate under various concentrations.
3rd, experimental result:
It is as follows to the inhibiting rate of PAR1 acceptors under the compounds of this invention various concentrations:
The half-inhibition concentration IC of derivative of the present invention50It is determined as follows:
Conclusion:Test compound of the present invention has obvious inhibitory action, Ca2+ oscillations to the PAR-1 calcium ion transports mediated
Antagonism IC50In the range of 0.76~1.1 μM, active, of the present invention compound quilt suitable with marketed drug SCH530348
It is accredited as PAR-1 receptor antagonists.
Biological test embodiment 2:The pharmacokinetics test of the compounds of this invention
Study the drug concentration of the embodiment of the present invention II -1, II -3 compound not in the same time in blood plasma and brain tissue, research
Pharmacokinetics behavior of the compounds of this invention in rat body, evaluates its characteristics of pharmacokinetics.
1. experimental animal
Healthy adult SD rat 6, male and female half and half are divided into 3 groups.Buy in the magnificent experimental animal technology of Beijing dimension tonneau
Co., Ltd.
2. dosage
This research is that experiment is administered in single dose.6 SD rats male and female half and half, are divided into 3 groups, every group 2, are respectively
SCH530348 groups, II -1 group, II -3 group.Fasting 12h before administration.Dosage is 5mg/kg.
3. medicine is prepared
Appropriate amount of drug is weighed, 0.5% sodium carboxymethylcellulose of addition is ground to sample and is uniformly suspended, and sample concentration is
2.0mg/ml, faces used time preparation.
4. the scheme of blood sampling
0min after rat administration, 5min, 15min, 25min, 40min, 1h, 2h, 4h, 8h, 12h, 24h eye sockets take blood
0.5mL, blood plasma is taken in 10 minutes in 4500rpm centrifugations.- 20 DEG C of refrigerators are preserved.
5. sample preparation
Plasma sample 50ul is taken, 20ul 1ug/ml diazepam inner mark solution is added, adds 10uL methanol, 400uL's
After ethyl acetate, abundant vortex 3min, 17000r/min centrifugation 10min take supernatant 300ul, after nitrogen drying, with 100uL's
Methanol:Water=1:1 redissolves, and direct injected carries out LC-MS analyses after abundant vortex 1min.
The pharmacokinetic parameter of the compounds of this invention such as following table:
Conclusion:The compound of the compounds of this invention II -3 half-life period in vivo and blood concentration are superior to marketed drug
SCH530348, and drug concentration ratio of II -3 compound in brain tissue/blood plasma will be far smaller than SCH530348, point out
The compounds of this invention II -3 passes through that blood-brain barrier ability is weaker, and the risk of cerebral hemorrhage may be greatly reduced, with preferably facing
Bed application prospect.
Claims (11)
1. compound or its stereoisomer, dynamic isomer, prodrug or pharmaceutically acceptable of the one kind with formula (II) structure
Salt or solvate:
Wherein:
R1Selected from heterocyclic radical, aryl or heteroaryl, wherein described heterocyclic radical, aryl or heteroaryl can be further optionally by one
It is individual or multiple selected from halogen, hydroxyl, cyano group, nitro, amido ,-NR3R4, it is alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, miscellaneous
Aryl ,-C (O) OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4Substituent replaced;Wherein described alkane
Epoxide, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl can further optionally by it is one or more selected from halogen, hydroxyl,
Cyano group, nitro, amido ,-NR4R5, alkoxy, alkyl, cycloalkyl, aryl, the substituent of heteroaryl replaced;
R2Selected from-C (O) OR3、-CN、-C(O)NR3R4, heterocyclic radical, aryl or heteroaryl, wherein described heterocyclic radical, aryl or miscellaneous
Aryl further optionally can be selected from halogen, hydroxyl, cyano group, nitro, amido ,-NR by one or more3R4, alkoxy, alkyl,
Cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR3、-OC(O)R3、-C(O)R3、-NHC(O)R3、-C(O)NR3R4Substitution
Base is replaced;Wherein described alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl can be further optionally by one
Or it is multiple selected from halogen, hydroxyl, cyano group, nitro, amido ,-NR3R4, alkoxy, alkyl, cycloalkyl, aryl, the substitution of heteroaryl
Base is replaced;
X is selected from CH or N;
N is selected from 0,1,2 or 3;
R3And R4Hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described heterocyclic radical,
Aryl or heteroaryl optionally further by it is one or more selected from halogen, hydroxyl, cyano group, nitro, amido, alkoxy, alkyl or
The substituent of cycloalkyl is replaced.
2. compound as claimed in claim 1 or its stereoisomer, dynamic isomer, prodrug or pharmaceutically acceptable salt
Or solvate:
Wherein:
R1Selected from heterocyclic radical, aryl or heteroaryl, wherein described heterocyclic radical, aryl or heteroaryl can be further optionally by one
It is individual or multiple selected from halogen, hydroxyl, cyano group, amido ,-NR3R4, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-
C(O)OR3、-NHC(O)R3、-C(O)NR3R4Substituent replaced;Wherein described alkoxy, alkyl, cycloalkyl, heterocycle
Base, aryl or heteroaryl further optionally can be selected from halogen, hydroxyl, cyano group, amido ,-NR by one or more3R4, alcoxyl
Base, alkyl, the substituent of cycloalkyl are replaced;
R2Selected from-C (O) OR3、-CN、-C(O)NR3R4Or heteroaryl, wherein described heteroaryl can be further optionally by one
Or it is multiple selected from halogen, hydroxyl, cyano group, amido ,-NR3R4, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C
(O)OR3、-NHC(O)R3、-C(O)NR3R4Substituent replaced;Wherein described alkoxy, alkyl, cycloalkyl, heterocyclic radical,
Aryl or heteroaryl further optionally can be selected from halogen, hydroxyl, cyano group, amido ,-NR by one or more3R4, alkoxy, alkane
Base, the substituent of cycloalkyl are replaced;
X is selected from CH or N;
N is selected from 0,1 or 2;
R3And R4Hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described heterocyclic radical,
Aryl or heteroaryl further optionally can be selected from halogen, hydroxyl, cyano group, amido, alkoxy, alkyl or ring by one or more
The substituent of alkyl is replaced.
3. compound according to claim 1 or 2 or its stereoisomer, dynamic isomer, prodrug can pharmaceutically connect
The salt or solvate received, it is characterised in that the compound preferably is selected from formula (III):
Wherein,
R1Selected from heterocyclic radical, aryl or heteroaryl, wherein described heterocyclic radical, aryl or heteroaryl can be further optionally by one
It is individual or multiple selected from halogen, hydroxyl, cyano group, amido ,-NR3R4, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-
C(O)OR3、-NHC(O)R3、-C(O)NR3R4Substituent replaced;Wherein described alkoxy, alkyl, cycloalkyl, heterocycle
Base, aryl or heteroaryl further optionally can be selected from halogen, hydroxyl, cyano group, amido ,-NR by one or more3R4, alcoxyl
Base, alkyl, the substituent of cycloalkyl are replaced;
R2Selected from-C (O) OR3、-CN、-C(O)NR3R4Or heteroaryl, wherein described heteroaryl can be further optionally by one
Or it is multiple selected from halogen, hydroxyl, cyano group, amido ,-NR3R4, alkoxy, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C
(O)OR3、-NHC(O)R3、-C(O)NR3R4Substituent replaced;Wherein described alkoxy, alkyl, cycloalkyl, heterocyclic radical,
Aryl or heteroaryl further optionally can be selected from halogen, hydroxyl, cyano group, amido ,-NR by one or more3R4, alkoxy, alkane
Base, the substituent of cycloalkyl are replaced;
R3And R4Hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described heterocyclic radical,
Aryl or heteroaryl further optionally can be selected from halogen, hydroxyl, cyano group, amido, alkoxy, alkyl or ring by one or more
The substituent of alkyl is replaced.
4. compound or its stereoisomer, dynamic isomer, prodrug according to any formulas of claim 1-3 or
Pharmaceutically acceptable salt or solvate, the wherein compound are selected from:
。
5. compound or its stereoisomer, dynamic isomer, prodrug or pharmaceutically acceptable salt according to claim 1
Or solvate, it is characterised in that the compound isomers are comprising all cis-trans-isomers that may be present in theory, along anti-
Isomer mixture, racemic modification, racemic mixture, enantiomter, diastereoisomer and non-corresponding isomers mixing
Thing;The compound pharmaceutically acceptable salt is the compound and inorganic acid/organic acid or inorganic base/organic base formation
Conventional non-toxic salts.
6. compound or its stereoisomer, dynamic isomer, prodrug or pharmaceutically acceptable salt according to claim 1
Or solvate, it is characterised in that there may be at least one hydrogen atom in the compound and replaced by D-atom or at least one
Individual carbon atom or fluorine atom are replaced by corresponding isotope.
7. a kind of pharmaceutical composition, it is characterised in that it is different that it contains compound or its solid described in claim 1-6 any one
Structure body, dynamic isomer, prodrug or pharmaceutically acceptable salt or solvate and pharmaceutically useful carrier.
8. compound described in claim 1 or its stereoisomer, dynamic isomer, prodrug or pharmaceutically acceptable salt or molten
Agent compound, or claim 7 described pharmaceutical composition are preparing thrombin receptor antagonist or platelet aggregation inhibitor, made
Standby treatment and/or prevention have the purposes in the medicine of related disorders with thrombin receptor.
9. purposes according to claim 8, wherein thrombin receptor antagonist are PAR1 receptor antagonists.
10. purposes according to claim 8, wherein described have related disorders to be selected from artery and venous blood with thrombin receptor
Bolt disease, acute coronary syndrome, ISR, stable angina cordis, arrhythmia, miocardial infarction, hypertension, heart failure,
PUD D, gastrointestinal disease, rheumatism, asthma, chronic hepatic fibrosis, tumour and the skins such as apoplexy, inflammatory disease, pulmonary embolism disease
Disease.
11. compound described in claim 1-6 any one or its stereoisomer, dynamic isomer, prodrug pharmaceutically may be used
The salt or solvate of receiving, and another cardiovascular drugs simultaneously or are respectively used to prepare treatment as combination product
Purposes in the medicine of angiocardiopathy, described another kind of cardiovascular drugs are to be selected from aspirin, clopidogrel, thiophene chlorine
The anti-platelet aggregation medicinals such as pyridine, Abciximab, tirofiban or eptifibatide.
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WO2019233473A1 (en) * | 2018-06-06 | 2019-12-12 | Yang Lun | Prophylactic and therapeutic drugs for fatty liver disease and related diseases |
CN110559294A (en) * | 2018-06-06 | 2019-12-13 | 杨仑 | Preventive and therapeutic drug for fatty liver disease and related diseases |
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WO2017181994A1 (en) | 2017-10-26 |
CN107304199B (en) | 2021-09-21 |
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