CN107304215A - Thiophene pyridine derivatives and its production and use - Google Patents
Thiophene pyridine derivatives and its production and use Download PDFInfo
- Publication number
- CN107304215A CN107304215A CN201610249883.9A CN201610249883A CN107304215A CN 107304215 A CN107304215 A CN 107304215A CN 201610249883 A CN201610249883 A CN 201610249883A CN 107304215 A CN107304215 A CN 107304215A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- compounds
- preparation
- follows
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to field of pharmaceutical chemistry technology, thiophene pyridine derivatives and its production and use are specifically disclosed.The present invention is transformed by the structure to thiophene pyridine compounds and their, has synthesized a series of thiophene pyridine derivatives noval chemical compounds, main to include carrying out into ester with aspirin and aspirin derivatives；Rapid metabolization is effective metabolite after compound enters in vivo; successfully avoid the metabolism of CYP2C19 enzymes; reactive compound directly can be metabolized as and play drug effect; so as to solve thiophene pyridine compounds and their resistance problem; effectively increase compound antithrombotic acitivity; and bleeding risk is not made significant difference, while this kind of compound has comparatively ideal protective effect to liver kidney, also there is potential therapeutic potential to other angiocardiopathies.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to thiophene pyridine derivatives and preparation method thereof and use
On the way.
Background technology
Thrombus disease be the lumen of vessels as caused by thrombus it is narrow and inaccessible and cause main organs occur ischemic and infraction and
Trigger the various diseases of dysfunction.Cause adhesion and gather that thrombotic factor has blood platelet on injured blood vessel wall surface
Collection, stasis of blood stream, the activation of clotting factor promote the formation of fibrin ferment and fibrinolytic low.Clinically for thrombus treatment
Medicine can be divided into 3 classes：Antiplatelet drug, anticoagulant and Thrombolytic Drugs.Antiplatelet drug has the effect for the treatment of and prevention concurrently, is
Main category in antithrombotic reagent.Antiplatelet drug refers to that can suppress hematoblastic sticks, assembles and release function, prevents
The formation of thrombus, the medicine for preventing and treating ischemic cardiovascular and cerebral vascular disease, periphery thrombotic disease.At present by antiplatelet drug
It is divided into three generations：Aspirin is the first generation, and Panaldine is the second generation（Thiophene pyridines, using adenosine diphosphate (ADP) acceptor as target spot
A class antiplatelet drug, the platelet aggregation-against being clinically most widely used at present, antithrombotic reagent/non-thiophene pyridine
Class）, such as clopidogrel/prasugrel, and a receptor antagonists of platelet membrane glycoprotein egg IIb/ III are the third generation.It is used as second generation thiophene
Fen pyridine derivatives, P2Y12-ADP receptor antagonists clopidogrel (clopidogrel) has preferable safety than Panaldine
Property, aspirin and chlorine adjoins the standard combination that Gray is current Antiplatelet therapy, the standard treated as antithrombotic reagent.
Clopidogrel and prasugrel are the higher P2Y12-ADP receptor antagonists of selectivity.ADP swashs hematoblastic
In work, combined by 3 acceptors on platelet membrane with blood platelet：P2Xl acceptors, P2Yl acceptors and P2Y12 acceptors, play weight
Act on.P2Y12 acceptors belong to a member of GPCR families, after ADP is combined with P2Y12 acceptors, the Liang Ge subunits of Gi albumen
(alpha Gi, beta gamma) exposure, alpha Gi subunits reduce cAMP by suppressing adenyl cyclase, led
III a of cause platelet glycoprotein IIb/ are complex activating, and beta gamma subunits can activate phosphatidylinositol3 3 kinase and be by one
Row Intracellular signals are transmitted, and cause platelet aggregation.P2Y12-ADP receptor antagonists by it is competitive or noncompetitive with
P2Y12 acceptors are combined, and reduce ADP binding site, are reduced platelet aggregation, are played a part of antithrombotic.
Another deficiency of clopidogrel is clopidogrel Resistant of increasing concern.Clinically, chlorine is resisted than Gray
(Clopidogrel resistance) is a kind of very universal phenomenon, and the incidence of this phenomenon is 4%-30%, in white man
Middle incidence is relatively low, in Black African secondly, and in Asian, and chlorine is than incidence highest that Gray resist, it is possible to be up to
55%.After generation chlorine is resisted than Gray, that brings is rear bright very serious, and cardiovascular event and the death rate significantly rise.Treated
The patient of clopidogrel Resistant is easier to occur thrombus in acute and subacute stent in journey, and Cardioversion sends out the death rate of survivor
Up to 15%-45%, again myocardial infarction rate be up to 60%-70%.
The mechanism for occurring clopidogrel Resistant is very complicated, wherein it is CytochromeP450 to compare the mechanism approved for everybody
The activity of enzyme.Research shows, enters blood by gastrointestinal tract first after oral clopidogrel.In blood, 85% chlorine pyrrole lattice
Thunder is directly metabolized into inactive metabolite by esterase and excreted, wherein only 15% clopidogrel by
CytochromeP450 enzymes are metabolized, and are participated in the enzyme of this metabolism and are included CYP3A4, CYP3A5, CYP2C9, CYPIA2, CYP2B6
And CYP2C19, thiolactone is formed, the metabolite with anticoagulant active is then metabolized as by CYP3A4 enzymes again, and play anti-
Blood coagulation drug effect.Increasing research shows that the function of patient's CYP2C19 enzymes of generation clopidogrel Resistant is weaker or lacks,
So as to cause clopidogrel can not be metabolized as thiolactone after entering in vivo, further it is metabolized as active metabolite and plays medicine
Effect.
The content of the invention
For the deficiencies in the prior art, it is an object of the invention to pass through the structure to thiophene pyridine compounds and their
Transformed, synthesized a series of thiophene pyridine derivatives noval chemical compounds, it is main to include spreading out with aspirin and aspirin
The biological derivative into ester；Rapid metabolization is effective metabolite after compound enters in vivo, successfully avoids CYP2C19 enzymes
Metabolism, directly can be metabolized as reactive compound and play drug effect, so as to solve the problems, such as clopidogrel Resistant.In addition, Ah Si
Its mechanism of action of woods, which mainly has, can make the acetylation of COX serine sites so as to block the combination of catalytic site and substrate, cause COX
Permanent deactivation, thrombocytopoiesis TXA2 is suppressed.Blood platelet does not have nucleus to recombine enzyme, hematoblastic COX mono-
Denier inactivation cannot be regenerated, therefore the suppression of aspirin on platelet is permanent, until blood platelet is regenerated.
In about 7~10 days hematoblastic life-spans, the blood platelet that 10% is there are about daily is regenerated, and aspirin 1 time a day is enough to maintain pair
The suppression of platelet T XA2 generations.Endothelial cell is karyocyte, deactivated to be recombined within a few hours.It is overall next
Say that aspirin can fully suppress blood platelet and have the synthesis for the TXA2 for promoting thrombus activity, and Human Umbilical Vein Endothelial Cells have anti-thrombus activity
PGI2 influences are little.What therefore low dose of aspirin was played is antithrombotic effect.Noval chemical compound is into internal rapid metabolization
Sulphur lactones, sulphur lactones is further metabolized as active metabolite.Aspirin and aspirin derivatives in vivo with effective generation
Thank to product to act synergistically, effectively increase compound antithrombotic acitivity, and bleeding risk is not made significant difference.It is simultaneously this kind of
Compound has comparatively ideal protective effect to liver kidney, also has potential therapeutic potential to other angiocardiopathies.
To achieve these goals, the invention provides a series of thiophene pyridine derivatives shown in below formula I, together
When additionally provide a series of compounds of formula I pharmaceutically acceptable salt or hydrate.
（Ⅰ）
Wherein R1For the alkyl containing 1-8 carbon, R4NR5（Wherein R4、R5For hydrogen or the alkyl of 1-10 carbon）Or methoxyl group；
R2For F, Cl, Br or I；
R3For、、、（Wave in structural formula
Line represents link position）.
Compound shown in the formula I includes levo-enantiomer, dextrorotatory antipode, raceme.
Representative compound is as follows in compound shown in the formula I：
Compound 1：
Compound 2：
Compound 3：
Compound 4：
Compound 5：
Compound 6：
Compound 7：
Compound 8：
Compound 9：
Compound 10：
Compound 11：
Compound 12：
Compound 13：
Compound 14：
Compound 15：
Compound 16：
Compound 17：
Compound 18：
Compound 19：
Compound 20：
Compound 21：
Compound 22：
Compound 23：
Compound 24：
Compound 25：
Compound 26：
Compound 27：
Compound 28：
Compound 29：
Compound 30：
Compound 31：
Compound 32：
Compound 33：
Compound 34：
Compound 35：
Compound 36：
Compound 37：
Compound 38：
Compound 39：
Compound 40：
Compound 41：
Second purpose of the present invention provides compound shown in formula I and can prepared by following 2 kinds of methods：
1st, in the basic conditions, key intermediate A：WithReact into corresponding
Ester, obtains compound of Formula I of the invention；
2nd, in acid condition, key intermediate B：WithReact into corresponding
Ester, obtains compound of Formula I of the invention；
The R being related in two above reaction equation1、R2And R3With R in hereinbefore mutual-through type I1、R2And R3Restriction.
Third aspect of the present invention is changed there is provided a kind of pharmaceutical composition, including according to the offer formula I of the present invention
Compound.Said composition further comprises one or more pharmaceutically acceptable carriers, excipient or diluent.
Said composition can be used for oral or parenteral routes, and the composition of oral administration includes conventional tablet, dispersible tablet, delayed
Release piece, controlled release tablet, capsule.The composition of parenteral routes includes sterile solution or injection sterile powder form or is adapted to use
In the sterile solution or the composition of injection sterile powder form that prepare parenteral routes.Said composition is to include containing according to this
The unit dose of compound shown in the formula I of invention, in an amount of from 1mg to 500mg.
The fourth aspect of the invention, compound shown in formula I is preventing and treating myocardial infarction, ischemic cerebral thrombus, occlusive
Complication caused by vasculitis and atherosclerosis and thromboembolism.Applied to having the apoplexy occurred in the recent period, myocardial infarction
Or the patient of peripheral arterial disease is made a definite diagnosis, the generation of atherosclerotic event can be reduced after treatment（Myocardial infarction, apoplexy and blood
Pipe is dead）.
Compared with prior art, the advantage and beneficial effect of technical solution of the present invention are：
L, the invention discloses a series of preparation of thiophene pyridine derivatives, it is main to include and aspirin and aspirin spread out
The biological derivative into ester；
2nd, rapid metabolization is effective metabolite after compound of the invention enters in vivo, successfully avoids the generation of CYP2C19 enzymes
Thank, directly can be metabolized as reactive compound and play drug effect, so as to solve thiophene pyridine compounds and their resistance problem；
3rd, there is anticoagulant active using aspirin and aspirin derivatives, artery and vein thrombus and cerebral thrombus shape can be suppressed
Into effect, make its platelet aggregation-against effect more preferably, bioavilability is higher.
Embodiment
Applicant will the present invention is described in further detail in conjunction with specific embodiments below, it is therefore intended that so that this
Art personnel more clearly understand the present invention, but herein below should not be construed in any way to the right to the present invention
The limitation of the claimed scope of claim.
Unless otherwise specified, the conventional hand that technological means used in embodiment is well known to the skilled person
Section.
Embodiment 1：The preparation method of compound 1, its synthetic line is as follows：
The levo form of intermediate 1 (10mmol) is dissolved in 20mL anhydrous methylene chlorides, at 0 DEG C or so, is added drop-wise to dissolved with intermediate 2
In the anhydrous methylene chloride of (11mmol) and triethylamine (15mmol), add rear temperature control and continue to stir 2 small at 0 DEG C or so
When.Reaction solution is poured into 60mL frozen water, extracted with ethyl acetate (100mL × 3), merges organic phase, organic phase saturation chlorine
Change sodium solution washing, anhydrous sodium sulfate drying, concentration is evaporated, and rapid column chromatography obtains target product compound 1.
Embodiment 2：The preparation method of compound 2 is as follows：
Prepare as described in Example 1, the difference is that the levo form of intermediate 1 is replaced with into the d-isomer of intermediate 1.
Embodiment 3：The preparation method of compound 3 is as follows：
Prepare as described in Example 1, the difference is that the levo form of intermediate 1 is replaced with into the raceme of intermediate 1.
Embodiment 4：The preparation method of compound 4, its synthetic line is as follows：
The raceme of intermediate 1 (10mmol) is dissolved in 20mL anhydrous acetonitriles, at 0 DEG C or so, is added drop-wise to dissolved with intermediate 3 (11mmol)
In the anhydrous acetonitrile of triethylamine (15mmol), add rear temperature control and continue to stir 4 hours at 0 DEG C or so.By reaction solution
Pour into 50mL frozen water, extracted with ethyl acetate (80mL × 3), merge organic phase, organic phase is washed with saturated nacl aqueous solution,
Anhydrous sodium sulfate drying, concentration is evaporated, and rapid column chromatography obtains target product compound 4.
Embodiment 5：The preparation method of compound 5 is as follows：
Prepare as described in Example 4, the difference is that the raceme of intermediate 1 is replaced with into the levo form of intermediate 1.
Embodiment 6：The preparation method of compound 6 is as follows：
Prepare as described in Example 4, the difference is that the raceme of intermediate 1 is replaced with into the d-isomer of intermediate 1.
Embodiment 7：The preparation method of compound 7, its synthetic line is as follows：
The raceme of intermediate 1 (10mmol) is dissolved in 20mL anhydrous acetonitriles, at 0 DEG C or so, is added drop-wise to dissolved with intermediate 4 (11mmol)
In the anhydrous acetonitrile of triethylamine (15mmol), add rear temperature control and continue to stir 4 hours at 0 DEG C or so.By reaction solution
Pour into 50mL frozen water, extracted with ethyl acetate (80mL × 3), merge organic phase, organic phase is washed with saturated nacl aqueous solution,
Anhydrous sodium sulfate drying, concentration is evaporated, and rapid column chromatography obtains target product compound 7.
Embodiment 8：The preparation method of compound 8 is as follows：
Prepare as described in Example 7, the difference is that the raceme of intermediate 1 is replaced with into the levo form of intermediate 1.
Embodiment 9：The preparation method of compound 9 is as follows：
Prepare as described in Example 7, the difference is that the raceme of intermediate 1 is replaced with into the d-isomer of intermediate 1.
Embodiment 10：The preparation method of compound 10, its synthetic line is as follows：
The levo form of intermediate 5 (10mmol) and intermediate 6 (11mmol) are dissolved in 20mL anhydrous acetonitriles, the concentrated sulfuric acid is added
（5mmol）, add rear temperature control and continue to stir 10 hours at 60 DEG C or so.Reaction solution is evaporated, residue is washed with water
Neutrality, target product compound 10 is being obtained by rapid column chromatography.
Embodiment 11：The preparation method of compound 11 is as follows：
Prepare as described in Example 10, the difference is that the levo form of intermediate 5 is replaced with into the d-isomer of intermediate 5.
Embodiment 12：The preparation method of compound 12 is as follows：
Prepare as described in Example 10, the difference is that the levo form of intermediate 5 is replaced with into the raceme of intermediate 5.
Embodiment 13：The preparation method of compound 13, its synthetic line is as follows：
The levo form of intermediate 7 (10mmol) and intermediate 8 (11mmol) are dissolved in 20mL anhydrous acetonitriles, the concentrated sulfuric acid is added
（5mmol）, add rear temperature control and continue to stir 10 hours at 60 DEG C or so.Reaction solution is evaporated, residue is washed with water
Neutrality, target product compound 13 is being obtained by rapid column chromatography.
Embodiment 14：The preparation method of compound 14 is as follows：
Prepare as described in Example 13, the difference is that the levo form of intermediate 7 is replaced with into the d-isomer of intermediate 7.
Embodiment 15：The preparation method of compound 15 is as follows：
Prepare as described in Example 13, the difference is that the levo form of intermediate 7 is replaced with into the raceme of intermediate 7.
Embodiment 16：The preparation method of compound 16, its synthetic line is as follows：
The raceme of intermediate 9 (10mmol) is dissolved in 20mL anhydrous methylene chlorides, at 0 DEG C or so, is added drop-wise to dissolved with intermediate 3
In the anhydrous methylene chloride of (11mmol) and triethylamine (15mmol), add rear temperature control and continue to stir 4 small at 0 DEG C or so
When.Reaction solution is poured into 50mL frozen water, extracted with ethyl acetate (80mL × 3), merges organic phase, organic phase saturation chlorination
Sodium solution is washed, and anhydrous sodium sulfate drying, concentration is evaporated, and rapid column chromatography obtains target product compound 16.
Embodiment 17：The preparation method of compound 17 is as follows：
Prepare as described in Example 16, the difference is that the raceme of intermediate 9 is replaced with into the levo form of intermediate 9.
Embodiment 18：The preparation method of compound 18 is as follows：
Prepare as described in Example 16, the difference is that the raceme of intermediate 9 is replaced with into the d-isomer of intermediate 9.
Embodiment 19：The preparation method of compound 19, its synthetic line is as follows：
The levo form of intermediate 9 (10mmol) is dissolved in 20mL anhydrous methylene chlorides, at 0 DEG C or so, is added drop-wise to dissolved with intermediate 4
In the anhydrous methylene chloride of (11mmol) and triethylamine (15mmol), add rear temperature control and continue to stir 4 small at 0 DEG C or so
When.Reaction solution is poured into 50mL frozen water, extracted with ethyl acetate (80mL × 3), merges organic phase, organic phase saturation chlorination
Sodium solution is washed, and anhydrous sodium sulfate drying, concentration is evaporated, and rapid column chromatography obtains target product compound 19.
Embodiment 20：The preparation method of compound 20 is as follows：
Prepare as described in Example 19, the difference is that the levo form of intermediate 9 is replaced with into the raceme of intermediate 9.
Embodiment 21：The preparation method of compound 21 is as follows：
Prepare as described in Example 19, the difference is that the levo form of intermediate 9 is replaced with into the d-isomer of intermediate 9.
Embodiment 22：The preparation method of compound 22, its synthetic line is as follows：
The levo form of intermediate 7 (10mmol) and intermediate 6 (11mmol) are dissolved in 20mL anhydrous acetonitriles, the concentrated sulfuric acid is added
（5mmol）, add rear temperature control and continue to stir 10 hours at 60 DEG C or so.Reaction solution is evaporated, residue is washed with water
Neutrality, target product compound 22 is being obtained by rapid column chromatography.
Embodiment 23：The preparation method of compound 23 is as follows：
Prepared by the method for embodiment 22, the difference is that the levo form of intermediate 7 is replaced with into the d-isomer of intermediate 7.
Embodiment 24：The preparation method of compound 24 is as follows：
Prepared by the method for embodiment 22, the difference is that the levo form of intermediate 7 is replaced with into the raceme of intermediate 7.
Embodiment 25：The preparation method of compound 25, its synthetic line is as follows：
The levo form of intermediate 10 (10mmol) and intermediate 8 (11mmol) are dissolved in 20mL anhydrous acetonitriles, the concentrated sulfuric acid is added
（5mmol）, add rear temperature control and continue to stir 10 hours at 80 DEG C or so.Reaction solution is evaporated, residue is washed with water
Neutrality, target product compound 25 is being obtained by rapid column chromatography.
Embodiment 26：The preparation method of compound 26 is as follows：
Prepared by the method for embodiment 25, the difference is that the levo form of intermediate 10 is replaced with into the d-isomer of intermediate 10.
Embodiment 27：The preparation method of compound 27 is as follows：
Prepared by the method for embodiment 25, the difference is that the levo form of intermediate 10 is replaced with into the raceme of intermediate 10.
Embodiment 28：The preparation method of compound 28, its synthetic line is as follows：
The raceme of intermediate 11 (10mmol) is dissolved in 20mL anhydrous methylene chlorides, at 0 DEG C or so, is added drop-wise to dissolved with intermediate 3
In the anhydrous methylene chloride of (11mmol) and triethylamine (15mmol), add rear temperature control and continue to stir 4 small at 0 DEG C or so
When.Reaction solution is poured into 50mL frozen water, extracted with ethyl acetate (80mL × 3), merges organic phase, organic phase saturation chlorination
Sodium solution is washed, and anhydrous sodium sulfate drying, concentration is evaporated, and rapid column chromatography obtains target product compound 28.
Embodiment 29：The preparation method of compound 29 is as follows：
Prepared by the method for embodiment 28, the difference is that the raceme of intermediate 11 is replaced with into the levo form of intermediate 11.
Embodiment 30：The preparation method of compound 30 is as follows：
Prepared by the method for embodiment 28, the difference is that the raceme of intermediate 11 is replaced with into the d-isomer of intermediate 11.
Embodiment 31：The preparation method of compound 31, its synthetic line is as follows：
The raceme of intermediate 11 (10mmol) is dissolved in 20mL anhydrous methylene chlorides, at 0 DEG C or so, is added drop-wise to dissolved with intermediate 4
In the anhydrous methylene chloride of (11mmol) and triethylamine (15mmol), add rear temperature control and continue to stir 4 small at 0 DEG C or so
When.Reaction solution is poured into 50mL frozen water, extracted with ethyl acetate (80mL × 3), merges organic phase, organic phase saturation chlorination
Sodium solution is washed, and anhydrous sodium sulfate drying, concentration is evaporated, and rapid column chromatography obtains target product compound 31.
Embodiment 32：The preparation method of compound 32 is as follows：
Prepared by the method for embodiment 31, the difference is that the raceme of intermediate 11 is replaced with into the d-isomer of intermediate 11.
Embodiment 33：The preparation method of compound 33 is as follows：
Prepared by the method for embodiment 31, the difference is that the raceme of intermediate 11 is replaced with into the levo form of intermediate 11.
Embodiment 34：The preparation method of compound 34, its synthetic line is as follows：
The raceme of intermediate 10 (10mmol) and intermediate 6 (11mmol) are dissolved in 20mL anhydrous acetonitriles, the concentrated sulfuric acid is added
（5mmol）, add rear temperature control and continue to stir 10 hours at 60 DEG C or so.Reaction solution is evaporated, residue is washed with water
Neutrality, target product compound 34 is being obtained by rapid column chromatography.
Embodiment 35：The preparation method of compound 35 is as follows：
Prepared by the method for embodiment 34, the difference is that the raceme of intermediate 10 is replaced with into the d-isomer of intermediate 7.
Embodiment 36：The preparation method of compound 36 is as follows：
Prepared by the method for embodiment 34, the difference is that the raceme of intermediate 10 is replaced with into the levo form of intermediate 10.
Embodiment 37：It is prepared by the monohydrate of compound 1
The 10.0g of compound 1 is taken, 60 DEG C of dissolvings are heated to 90% aqueous acetone solution 100ml, 1% is added（W/V）Activated carbon, insulation
20min is stirred, filtering, freezing crystallization 12 hours, filtering obtains the monohydrate of compound 1.
Embodiment 38：It is prepared by the trihydrate of compound 15
The 10.0g of compound 15 is taken, 60 DEG C of dissolvings are heated to 90% acetonitrile solution 80ml, 1% is added（W/V）Activated carbon, insulation
20min is stirred, filtering, freezing crystallization 12 hours, filtering obtains the trihydrate of compound 15.
Embodiment 39：It is prepared by the pentahydrate of compound 10
The 10.0g of compound 10 is taken, 60 DEG C of dissolvings are heated to 80% isopropanol water solution 100ml, 1% is added（W/V）Activated carbon,
Insulated and stirred 20min, filtering, freezing crystallization 12 hours, filtering obtains the pentahydrate of compound 10.
Embodiment 40：It is prepared by the hydrochloride of compound 1
The 10.0g of compound 1 is taken, 60 DEG C of dissolvings are heated to acetone 100ml, concentrated hydrochloric acid regulation pH to 3, insulated and stirred is added
20min, filtering, freezing crystallization 12 hours, filtering obtains the hydrochloride of compound 1.
Embodiment 41：It is prepared by the fumarate of compound 5
The 10.0g of compound 5 is taken, 60 DEG C of dissolvings are heated to acetonitrile 100ml, fumaric acid 5g, insulated and stirred 20min, mistake is added
Filter, freezing crystallization 24 hours, filtering obtains the fumarate of compound 5.
Embodiment 42：It is prepared by the sulfate of compound 10
The 10.0g of compound 10 is taken, 60 DEG C of dissolvings are heated to tetrahydrofuran 80ml, concentrated sulfuric acid 5ml, insulated and stirred is added
20min, filtering, freezing crystallization 24 hours, filtering obtains the sulfate of compound 10.
The pharmacological effect research of the generalformulaⅰcompound (obtained product in embodiment) of the present invention
1. oral thiophene pyridine derivate is to rat platelet aggregation inhibitory action
Male Wistar rat（There is provided by Jiangsu Province drug safety evaluation center）, body weight, 200-250g is randomly divided into 5 groups, cloudy
Property control group (0.5% CMC-Na, 1.Oml/kg, p.o.), positive controls（Prasugrel, founding moral medical sci-tech by Jinan has
Limit company provides, and prepares in 0.5%CMC-Na Shens, 30mg/kg, p.o.), compound is low, in, high three dosage groups（Prepare
In 0.5%CMC-Na, 1.Oml/kg, p.o.）, every group of 8-10 animal.Oral 0.5% CMC-Na of animal, positive drug or tested
Medicine, respectively at before administration and 0.5, l, 2,4,8h after administration, afterbody takes blood.Prepare platelet rich plasma.By hematoblastic meter
Number is adjusted to 2 × 105μ l, blank control is used as using platelet poor plasma.Using ADP as derivant, ADP is added to the blood prepared
Platelet suspension, final concentration of 5 μ l.The trial drug 0.5 of 150 μ l platelet suspensions and various concentrations is separately added into 96 orifice plates
μ l, are incubated after 5min and 20 μM of ADP are added per hole by 37 DEG C, using turbidimetry, are surveyed using LBY-NJ four-ways platelet aggregation instrument
Determine platelet aggregation percentage.Calculate Platelet aggregation inhibitor percentage.
The inhibitory action of thiophene pyridine derivate prepared by the oral embodiment of table 1. to rat platelet aggregation
Conclusion：Test compound is respectively provided with different degrees of inhibitory action, wherein compound 8, chemical combination to rat platelet aggregation
Thing 15, compound 19, compound 20, compound 24, compound 29, compound 33, compound 36 press down to rat platelet aggregation
It is often suitable with prasugrel, compound 1, compound 5, compound 10, compound 16, compound 17, compound 22, compound 25
It is more excellent to Platelet aggregation inhibitor effect compared to prasugrel.
2. the influence of thiophene pyridine derivate prepared by oral embodiment 1-12 to the rat bleeding time
Male Wistar rat（There is provided by Jiangsu Province's drug safety assessment centers）, body weight, 200-250g is randomly divided into 5 groups, cloudy
Property control group (0.5% CMC-Na, 1.Oml/kg, p.o.), positive controls（Prasugrel, founding moral medical sci-tech by Jinan has
Limit company provides, and prepares in 0.5%CMC-Na, 30mglkg, p.o.）, basic, normal, high three dosage groups of compound（Prepare
In 0.5%CMC-Na, 1.Oml/kg, p.o.）, every group of 8-10 animal.
Oral 0.5% CMC-Na of animal, prasugrel or test medicine be after l hours, away from cutting off mouse with blade at tail point 2mm
Tail, is sucked blood to 1min without bloodstain with filter paper every 15s, records the bleeding time.
Table 2.Influence of the oral test compound to the rat bleeding time
| Treatment | Bleeding time min |
| Negative control | 15±3 |
| Prasugrel | 36±6 |
| Compound 1 | —— |
| 10mg/kg | 39±10 |
| 5mg/kg | 26±6 |
| 1mg/kg | 16±2 |
| Compound 5 | —— |
| 10mg/kg | 36±8 |
| 5mg/kg | 28±7 |
| 1mg/kg | 18±5 |
| Compound 8 | —— |
| 10mg/kg | 30±7 |
| 5mg/kg | 25±5 |
| 1mg/kg | 17±3 |
| Compound 10 | —— |
| 10mg/kg | 40±9 |
| 5mg/kg | 27±6 |
| 1mg/kg | 17±6 |
| Compound 15 | —— |
| 10mg/kg | 29±7 |
| 5mg/kg | 22±6 |
| 1mg/kg | 16±4 |
| Compound 16 | —— |
| 10mg/kg | 36±8 |
| 5mg/kg | 26±5 |
| 1mg/kg | 17±6 |
| Compound 17 | —— |
| 10mg/kg | 35±12 |
| 5mg/kg | 27±7 |
| 1mg/kg | 19±7 |
| Compound 19 | —— |
| 10mg/kg | 26±6 |
| 5mg/kg | 20±5 |
| 1mg/kg | 14±5 |
| Compound 20 | —— |
| 10mg/kg | 30±9 |
| 5mg/kg | 24±8 |
| 1mg/kg | 17±7 |
| Compound 22 | —— |
| 10mg/kg | 23±8 |
| 5mg/kg | 19±6 |
| 1mg/kg | 17±4 |
| Compound 24 | —— |
| 10mg/kg | 38±10 |
| 5mg/kg | 25±6 |
| 1mg/kg | 18±4 |
| Compound 25 | —— |
| 10mg/kg | 36±9 |
| 5mg/kg | 27±5 |
| 1mg/kg | 19±4 |
| Compound 29 | —— |
| 10mg/kg | 26±6 |
| 5mg/kg | 20±5 |
| 1mg/kg | 13±5 |
| Compound 33 | —— |
| 10mg/kg | 29±6 |
| 5mg/kg | 20±9 |
| 1mg/kg | 15±6 |
| Compound 36 | —— |
| 10mg/kg | 26±9 |
| 5mg/kg | 21±7 |
| 1mg/kg | 15±6 |
Conclusion：Compared with negative control group, after Wistar Oral Administration in Rats test-compounds, there be different degrees of prolong in the bleeding time
It is long, wherein taking compound 8, compound 15, compound 19, compound 20, compound 22, compound 29, compound 33, chemical combination
The rat bleeding time of thing 36 is shorter compared with prasugrel, shows that such compound has less bleeding risk.
Claims (8)
1. compounds of formula I：
。
2. compounds of formula I according to claim 1, it is characterised in that：The R1For the alkyl containing 1-8 carbon,
R4NR5Wherein R4、R5For hydrogen or the alkyl or methoxyl group of 1-10 carbon；R2For F, Cl, Br or I；
R3For、、、Wave in structural formula
Represent link position.
3. compounds of formula I according to claim 1 or claim 2, it is characterised in that including compounds of formula I pharmaceutically
Acceptable salt or hydrate.
4. the compounds of formula I according to claim 1,2,3, it is characterised in that including compound shown in the formula I
Levo-enantiomer, dextrorotatory antipode, raceme.
5. the preparation method of compounds of formula I according to claim 1 or claim 2：In the basic conditions, key intermediate A：WithCorresponding ester is reacted into, compound of Formula I of the invention is obtained.
6. the preparation method of compounds of formula I according to claim 1 or claim 2：In acid condition, key intermediate B：WithCorresponding ester is reacted into, compound of Formula I of the invention is obtained.
7. provide compound shown in formula I according to claim 1,2,3, it is characterised in that compound shown in formula I includes one kind
Or the composition of a variety of pharmaceutically acceptable carriers, excipient or diluent.
8. purposes of the compounds of formula I described in claim 1,2,3 in preventing or treating the medicine of thrombus.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610249883.9A CN107304215A (en) | 2016-04-20 | 2016-04-20 | Thiophene pyridine derivatives and its production and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610249883.9A CN107304215A (en) | 2016-04-20 | 2016-04-20 | Thiophene pyridine derivatives and its production and use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107304215A true CN107304215A (en) | 2017-10-31 |
Family
ID=60152852
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610249883.9A Pending CN107304215A (en) | 2016-04-20 | 2016-04-20 | Thiophene pyridine derivatives and its production and use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107304215A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022028347A1 (en) * | 2020-08-03 | 2022-02-10 | 天地恒一制药股份有限公司 | Optically active 2-hydroxyltetrahydrothienopyridine derivative, and preparation method therefor and use thereof |
| WO2023202383A1 (en) * | 2022-04-19 | 2023-10-26 | 中荣凯特（北京）生物科技有限公司 | Tetrahydrothienopyridine deuterated derivative, preparation method therefor, and pharmaceutical use thereof |
Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101591344A (en) * | 2008-05-27 | 2009-12-02 | 连云港恒邦医药科技有限公司 | A kind of antithrombotic compound, Preparation Method And The Use |
| CN101684124A (en) * | 2008-09-22 | 2010-03-31 | 王振 | Novel compound with blood coagulation resisting function |
| CN101974015A (en) * | 2010-10-11 | 2011-02-16 | 天津药物研究院 | Ester compound and preparation method and application thereof |
| CN102002053A (en) * | 2009-09-02 | 2011-04-06 | 陕西合成药业有限公司 | Tetrahydro thienopyridine derivative for treating |
| WO2011079407A1 (en) * | 2009-12-28 | 2011-07-07 | 北京益君康医药技术有限公司 | New compounds having potency to inhibit blood clotting |
| CN102120744A (en) * | 2010-02-02 | 2011-07-13 | 江苏威凯尔医药科技有限公司 | Optical-activity 2-hydroxytetrahydrothienopyridine derivative, preparation method and application thereof in pharmacy |
| CN102199163A (en) * | 2011-04-01 | 2011-09-28 | 中国药科大学 | 2-hydroxy tetrahydrothiophene derivative, preparation method thereof and application thereof in pharmacy |
| CN102229616A (en) * | 2011-05-06 | 2011-11-02 | 伍复健 | Tetrahydrothieno pyridine derivative, and preparation method and purpose thereof |
| WO2012139422A1 (en) * | 2011-04-14 | 2012-10-18 | Yan Xiaojing | Novel anti-platelet compound addition salt |
| CN103068383A (en) * | 2010-08-26 | 2013-04-24 | Ipca实验室有限公司 | Methods for the treatment or prophylaxis of thrombosis or embolism |
| CN103254211A (en) * | 2012-02-17 | 2013-08-21 | 江苏威凯尔医药科技有限公司 | Method for preparing vicagrel and derivatives thereof |
| CN103694250A (en) * | 2012-09-28 | 2014-04-02 | 武汉启瑞药业有限公司 | Thienopyridine derivatives, and preparation methods and medical use thereof |
| CN104245707A (en) * | 2011-06-27 | 2014-12-24 | Ipca实验室有限公司 | Anti-thrombotic compounds |
| CN105153192A (en) * | 2014-09-02 | 2015-12-16 | 南京曼杰生物科技有限公司 | Substituted tetrahydrothienopyridine derivative and application thereof |
-
2016
- 2016-04-20 CN CN201610249883.9A patent/CN107304215A/en active Pending
Patent Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101591344A (en) * | 2008-05-27 | 2009-12-02 | 连云港恒邦医药科技有限公司 | A kind of antithrombotic compound, Preparation Method And The Use |
| CN101684124A (en) * | 2008-09-22 | 2010-03-31 | 王振 | Novel compound with blood coagulation resisting function |
| CN102002053A (en) * | 2009-09-02 | 2011-04-06 | 陕西合成药业有限公司 | Tetrahydro thienopyridine derivative for treating |
| WO2011079407A1 (en) * | 2009-12-28 | 2011-07-07 | 北京益君康医药技术有限公司 | New compounds having potency to inhibit blood clotting |
| CN102120744A (en) * | 2010-02-02 | 2011-07-13 | 江苏威凯尔医药科技有限公司 | Optical-activity 2-hydroxytetrahydrothienopyridine derivative, preparation method and application thereof in pharmacy |
| CN103068383A (en) * | 2010-08-26 | 2013-04-24 | Ipca实验室有限公司 | Methods for the treatment or prophylaxis of thrombosis or embolism |
| CN101974015A (en) * | 2010-10-11 | 2011-02-16 | 天津药物研究院 | Ester compound and preparation method and application thereof |
| CN102199163A (en) * | 2011-04-01 | 2011-09-28 | 中国药科大学 | 2-hydroxy tetrahydrothiophene derivative, preparation method thereof and application thereof in pharmacy |
| WO2012139422A1 (en) * | 2011-04-14 | 2012-10-18 | Yan Xiaojing | Novel anti-platelet compound addition salt |
| CN102229616A (en) * | 2011-05-06 | 2011-11-02 | 伍复健 | Tetrahydrothieno pyridine derivative, and preparation method and purpose thereof |
| CN104245707A (en) * | 2011-06-27 | 2014-12-24 | Ipca实验室有限公司 | Anti-thrombotic compounds |
| CN103254211A (en) * | 2012-02-17 | 2013-08-21 | 江苏威凯尔医药科技有限公司 | Method for preparing vicagrel and derivatives thereof |
| CN103694250A (en) * | 2012-09-28 | 2014-04-02 | 武汉启瑞药业有限公司 | Thienopyridine derivatives, and preparation methods and medical use thereof |
| CN105153192A (en) * | 2014-09-02 | 2015-12-16 | 南京曼杰生物科技有限公司 | Substituted tetrahydrothienopyridine derivative and application thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022028347A1 (en) * | 2020-08-03 | 2022-02-10 | 天地恒一制药股份有限公司 | Optically active 2-hydroxyltetrahydrothienopyridine derivative, and preparation method therefor and use thereof |
| CN114286823A (en) * | 2020-08-03 | 2022-04-05 | 天地恒一制药股份有限公司 | Optically active 2-hydroxy tetrahydrothienopyridine derivative and preparation method and application thereof |
| CN114286823B (en) * | 2020-08-03 | 2023-11-28 | 天地恒一制药股份有限公司 | Optically active 2-hydroxy tetrahydrothiophene pyridine derivative and preparation method and application thereof |
| WO2023202383A1 (en) * | 2022-04-19 | 2023-10-26 | 中荣凯特（北京）生物科技有限公司 | Tetrahydrothienopyridine deuterated derivative, preparation method therefor, and pharmaceutical use thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104837833B (en) | The crystal formation of XIA factor inhibitors | |
| CN103694250B (en) | Thiophene pyridine derivatives and preparation method thereof and medicinal use | |
| HUE030540T2 (en) | New 5-aminotetrahydroquinoline-2-carboxylic acids und their use | |
| EA027244B1 (en) | Alkoxy pyrazoles as soluble guanylate cyclase activators | |
| CN103068383A (en) | Methods for the treatment or prophylaxis of thrombosis or embolism | |
| CA2920410A1 (en) | Thienopiperidine derivative and use thereof | |
| CN109153672A (en) | TRPV4 antagonist | |
| CN107304215A (en) | Thiophene pyridine derivatives and its production and use | |
| CN104662022A (en) | Means and method for treating solid tumours | |
| CN109503548B (en) | Butylphthalide derivative and preparation method and application thereof | |
| CN106554303A (en) | Thienopyridine analog derivative and its production and use | |
| CN106554368A (en) | Thienopyridine analog derivative and its production and use | |
| WO2017107262A1 (en) | Par-1 inhibitor based on terpene derivative and preparation method and use in treatment of thrombotic diseases thereof | |
| Salman et al. | New Gemcitabine Derivatives as potent in vitro α-Glucosidase Inhibitors | |
| CN107922448B (en) | Deuterated thienopiperidine derivative, preparation method and application thereof | |
| CN107935972A (en) | 5 [2 hydroxyl 3 (isopropylamine base) propoxyl group] benzofuran derivatives and its application | |
| CN107304216A (en) | Thiophene pyridine derivatives and its production and use | |
| CN104530029B (en) | Heterocyclic compounds as factor Xa inhibitors as well as using methods and application of heterocyclic compounds | |
| CN104974187A (en) | Phenanthroline derivative, preparation method and application thereof | |
| US20220152077A1 (en) | Adenosine receptor agonists | |
| CN103554087A (en) | Dabigatran derivative, as well as preparation method and antithrombus application thereof | |
| CN111670188B (en) | Compounds and compositions for treating fibrosis | |
| CN108203449A (en) | A kind of reversible proton pump inhibitor and its preparation method and application | |
| CN103420983B (en) | Dabigatran derivative, and preparation method and application thereof | |
| CN103420984B (en) | Dabigatran derivative used as prodrug, and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: Room 30803, Haijia Yunding commercial and residential building, No.2, Gaoxin Third Road, high tech Zone, Xi'an City, Shaanxi Province Applicant after: Huachuang Synthetic Pharmaceutical Co.,Ltd. Address before: Room 30803, Haijia Yunding commercial and residential building, No.2, Gaoxin Third Road, high tech Zone, Xi'an City, Shaanxi Province Applicant before: SHAANXI SYNTHETIC PHARMACEUTICAL Co.,Ltd. |
|
| CB02 | Change of applicant information | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20210122 Address after: Room 30803, Haijia Yunding commercial and residential building, No.2, Gaoxin Third Road, high tech Zone, Xi'an City, Shaanxi Province Applicant after: SHAANXI SYNTHETIC PHARMACEUTICAL Co.,Ltd. Address before: Room 30803, Haijia Yunding commercial and residential building, No.2, Gaoxin Third Road, Xi'an City, Shaanxi Province, 710075 Applicant before: SHAANXI SYNTHETIC PHARMACEUTICAL Co.,Ltd. Applicant before: JIANGSU TIANDIRENHE PHARMACEUTICAL Co.,Ltd. |
|
| TA01 | Transfer of patent application right | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20171031 |
|
| WD01 | Invention patent application deemed withdrawn after publication |