CN106467546A - Clopidogrel derivant and its production and use - Google Patents
Clopidogrel derivant and its production and use Download PDFInfo
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Abstract
The present invention relates to a kind of clopidogrel derivant and its production and use, clopidogrel derivant of the present invention has the structure shown in lower formula (I), wherein R1、R2、R3、R4, m and n be as defined in the claims, present invention additionally comprises the preparation method of formula (I) compound, its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer, containing their pharmaceutical composition and its purposes as medicine, especially for for preventing or treating atheromatosiss, myocardial infarction, apoplexy, ischemic cerebral thrombosiss, peripheral arterial disease, acute coronary syndrome or the postoperative thrombosiss of calcification score.
Description
Technical field
The present invention relates to clopidogrel derivant and its pharmaceutically acceptable salt of non-toxic, solvated compoundses, racemic mixture or enantiomer, its preparation method, containing their pharmaceutical composition and its purposes as medicine, especially for prevention or treatment atheromatosiss, myocardial infarction, apoplexy, ischemic cerebral thrombosiss, peripheral arterial disease, acute coronary syndrome or the postoperative thrombosiss of calcification score.
Background technology
Thrombus disease is that the lumen of vessels being caused by thrombosis is narrow and inaccessible and lead to main organs to occur ischemia and infraction to cause the various diseases of malfunction.Thrombotic factor is led to have adhesion on injured blood vessel wall surface for the platelet and gathering, stasis of blood stream, the activation of thrombin to promote the formation of thrombin and fibrinolytic low.The medicine being clinically used for thrombus treatment 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 the main category in antithrombotic reagent.Antiplatelet drug refers to that can suppress hematoblastic sticks, assembles and release function, stops the formation of thrombosis, for preventing and treating the medicine of ischemic cardiovascular and cerebral vascular disease, periphery thrombotic disease.At present antiplatelet drug is divided into three generations：Aspirin is the first generation, thiophene chloropyridine is the second filial generation (thiophene pyridines, a class antiplatelet drug with adenosine diphosphate (ADP) receptor as target spot, the current antiplatelet aggregation being clinically most widely used, antithrombotic reagent/non-thiophene pyridines), as clopidogrel/prasugrel, and platelet membrane glycoprotein egg IIb/IIIa receptor antagonist is the third generation.As second filial generation thiophene pyridine derivatives, P2Y12-ADP receptor antagonist clopidogrel（clopidogrel）There is preferable safety than thiophene chloropyridine, clopidogrel is the anti-platelet aggregation medicine being most widely used in the world at present.
The another not enough of clopidogrel is clopidogrel Resistant of increasing concern.Clinically, clopidogrel Resistant (Clopidogrel
Resistance it is) a kind of very universal phenomenon, the incidence rate of this phenomenon is 4%-30%, and in white man, incidence rate is relatively low, in Black African secondly, and in Aisan, incidence rate highest that chlorine is resisted than Gray is it is possible to up to 55%.After occurring chlorine to resist than Gray, the consequence brought is very serious, and cardiovascular event and mortality rate significantly rise.In therapeutic process, the patient of clopidogrel Resistant is easier to occur thrombosis in acute and subacute stent, and Cardioversion sends out the mortality rate up to 15%～45% of survivor, myocardial infarction rate up to 60%～70% again.
The mechanism that clopidogrel Resistant occurs is very complicated, wherein compares the activity that the mechanism for everybody accreditation is Cytochrome P450 enzyme.Research shows, enters blood by gastrointestinal tract first after oral clopidogrel.In blood, 85% clopidogrel is directly metabolized into inactive metabolite by esterase and excretes, by the metabolism of CytochromeP450 enzyme institute, the enzyme participating in this metabolism includes CYP3A4, CYP3A5 to wherein only 15% clopidogrel, CYP2C9, CYP1A2, CYP2B6 and CYP2C19, form thiolactone, then it is the metabolite with anticoagulant active by CYP3A4 enzyme metabolism again, and play anticoagulation drug effect.Increasing research shows, the function of patient's CYP2C19 enzyme of generation clopidogrel Resistant is weaker or lacks, thus cannot metabolism be thiolactone after causing clopidogrel entrance internal, further metabolism plays drug effect for active metabolite.
Therefore it may still be desirable to provide that a kind of oral availability is high, anticoagulant effect is notable, be not even fixed against CYP2C19 enzymatic activity can metabolism active drugs clopidogrel derivant.
Content of the invention：
It is an object of the invention to provide a kind of oral availability is high, anticoagulant effect is notable, be not even fixed against CYP2C19 enzymatic activity can metabolism active drugs clopidogrel derivant.
Summary of the invention：
First aspect present invention provides to be had with the clopidogrel derivant shown in following formula (I) or its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer.
The method that second aspect present invention provides clopidogrel derivant or its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer described in preparation first aspect present invention.
Second aspect present invention provides clopidogrel derivant or its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer described in preparation first aspect present invention.
Fourth aspect present invention provides clopidogrel derivant described in first aspect present invention or its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer and applies in preparation prevention or treatment atheromatosiss, myocardial infarction, apoplexy, ischemic cerebral thrombosiss, peripheral arterial disease, acute coronary syndrome or the postoperative thrombotic medicine of calcification score.
Fifth aspect present invention provides a kind of pharmaceutical composition, and it includes clopidogrel derivant described in the first aspect present invention of clinical effective dose or its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer and optional pharmaceutically acceptable carrier.
Brief description
Fig. 1 is test example 3 Pharmacokinetic Evaluation
Detailed Description Of The Invention
First aspect present invention provides to be had with the clopidogrel derivant shown in following formula (I) or its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer,
Wherein：
R1It is hydrogen atom, halogen, cyano group, alkyl, haloalkyl, hydroxyalkyl, carboxyl or carboxylic acid ester groups；
M is 0 or 2；
N is 0 to 8 integer；
R2Or R3It is independently hydrogen or C1-C6
Alkyl or optionally substituted C1-C6
Alkyl；And R4For
Or succinic acid（Wave represents link position）；
Wherein R5For l-amino acid side-chain radical, described l-amino acid is selected from：Lysine, arginine, histidine, ornithine, 2,3- diaminopropionic acid, 2,4- diaminopropionic acid, alanine, L-Valine, leucine, isoleucine, Phenylalanine, tryptophan, Methionine, glycine, serine, threonine, cysteine, tyrosine, agedoite, L-Glutamine, aspartic acid, glutamic acid.
Preferably, above-mentioned clopidogrel derivant is as shown in Formula II：
Wherein, group R1、R2、R3、R4And m and n such as claim 1 is defined.
According to certain embodiments of the present invention, the present invention provides clopidogrel derivant or its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer, wherein, R1It is for Cl；R4ForOr succinic acid（Wave represents link position）, m is 1；N is 0；
Wherein R5For amino acid side groups, described aminoacid is selected from：Lysine, arginine, histidine, ornithine, glycine.
Described aminoacid can be D type, L-type and DL type.
According to certain embodiments of the present invention, the present invention provides clopidogrel derivant or its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer, and wherein, described clopidogrel derivant includes following compounds：
5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -2- base 2,6-diaminocaproic acid（Compound 1）
Compound 1-1
Compound 1-2
Compound 1-3
5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -2 base -2- amino -5- guanidinopentanoic acid（Compound 2）
Compound 2-1
Compound 2-2
Compound 2-3
5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -2- base 2- amino -3-（1H- Imidazopyridine -2- base）Ethyl propionate（Compound 3）
Compound 3-1
Compound 3-2
Compound 3-3
5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -2 base -2- aminovaleric acid（Compound 4）
Compound 4-1
Compound 4-2
Compound 4-3
5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -2 bases-glycine（Compound 5）
Compound 5
5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -4- ketobutyric acid（Compound 6）
Compound 6
.
Term used herein " pharmaceutical salts " refers to retain the expected physiologically active of parent compound without producing the salt of any unexpected toxic and side effects, for example：Hydrochlorate, hydrobromate, sulfate, disulfate, phosphate, nitrate, and acetate, oxalates, tartrate, succinate, malate, benzoate, embonate, alginate, mesylate, naphthalene sulfonate, sodium salt, magnesium salt, potassium salt, calcium salt, choline salt, meglumine salt etc..
Described solvated compoundses are hydrate, alcohol adduct etc..
Selecting and preparing pharmaceutically acceptable salt or solvated compoundses etc. is technology as well known to those skilled in the art.
According to the specific embodiment of the present invention, the compound 1 of the present invention, compound 2, compound 3, compound 4, compound 5 can be prepared by following manner：
By (S)-(the chloro- phenyl of 2-)-(2- hydroxyl -6; 7- dihydro -4H- thiophene [3; 2-c] pyridine -5- base)-methyl acetate is in anhydrous organic solvent; with protected amino acid, Carbodiimide condensation reagent, DMAP stirring reaction 1～24 hour at a temperature of -20～60 DEG C; preferably 4～12 hours; concentrate; obtain compound 1, compound 2, compound 3, compound 4, compound 5; its pharmaceutical salts is convertible into by proper method, preparing different salt is technology as well known to those skilled in the art.
Above-mentioned anhydrous organic solvent is selected from：Dichloromethane, dehydrated alcohol, isopropanol, acetonitrile, DMF, dioxane, oxolane, ethyl acetate etc. be single or mixed solvent, preferably dichloromethane；
Above-mentioned reaction temperature is -20～60 DEG C, preferably 20～30 DEG C；
Above-mentioned Carbodiimide condensation reagent is DCC, DIC or EDC, preferably DCC；
Above-mentioned protected amino acid is preferably：Nα- tertbutyloxycarbonyl-Nε- tertbutyloxycarbonyl -1B, Nα- tertbutyloxycarbonyl-L-Arginine hydrochlorate, Nα- tertbutyloxycarbonyl-Nim- trityl-L-histidine, 2-N- tertbutyloxycarbonyl -, 3-N- tertbutyloxycarbonyl-diaminopropionic acid, N- tertbutyloxycarbonyl-N'- (2- benzyloxycarbonylchloride base)-L-Orn, 2-N- tertbutyloxycarbonyl -, 4-N- tertbutyloxycarbonyl -2,4- diaminopropionic acid, Nα- tertbutyloxycarbonyl-alanine, Nα- tertbutyloxycarbonyl-L-Valine, Nα- tertbutyloxycarbonyl-leucine, Nα- tertbutyloxycarbonyl-isoleucine, Nα- tertbutyloxycarbonyl-Phenylalanine, Nα- tertbutyloxycarbonyl-tryptophan, Nα- tertbutyloxycarbonyl-Methionine, Nα- tertbutyloxycarbonyl-glycine, Nα- tertbutyloxycarbonyl-O- the tert-butyl group-serine, Nα- tertbutyloxycarbonyl-O- the tert-butyl group-threonine, Nα- tertbutyloxycarbonyl cysteine (S- trityl), Nα- tertbutyloxycarbonyl tyrosine (the O- tert-butyl group), Nα- tertbutyloxycarbonyl-agedoite, Nα- tertbutyloxycarbonyl-L-Glutamine, Nα- tertbutyloxycarbonyl-aspartic acid -4- the tert-butyl ester, Nα- tertbutyloxycarbonyl-glutamic acid -5- the tert-butyl ester；
Reactant dosage molar ratio example is; (S)-(the chloro- phenyl of 2-)-(2- hydroxyl -6; 7- dihydro -4H- thiophene [3; 2-c] pyridine -5- base)-methyl acetate: protected amino acid: Carbodiimide condensation reagent: DMAP=1: 0.5～5: 1～4: 0.05～0.5, more preferably ratio is 1: 0.9～1: 1～2.2: 0.05～0.2；
According to the specific embodiment of the present invention, the compound 6 of the present invention can be prepared by following manner：
Add (S)-(the chloro- phenyl of 2-)-(2- hydroxyl -6 in organic solvent, 7- dihydro -4H- thiophene [3,2-c] pyridine -5- base)-methyl acetate, succinic anhydrides (i.e. succinic anhydride) and alkali, reacted at -50～150 DEG C, obtained compound 6.
The consumption of above-mentioned organic solvent is 2～100 times of (S)-(the chloro- phenyl of 2-)-(2- hydroxyl -6,7- dihydro -4H- thiophene [3,2-c] pyridine -5- base)-methyl acetate weight.
Above-mentioned reaction temperature is 0～120 DEG C.
The consumption of above-mentioned alkali is 0.01～10 times of (S)-(the chloro- phenyl of 2-)-(2- hydroxyl -6,7- dihydro -4H- thiophene [3,2-c] pyridine -5- base)-methyl acetate molal quantity.
Above-mentioned organic solvent is oxolane, ethyl acetate, dichloromethane, at least one in pyridine and toluene.
Above-mentioned alkali includes organic base or inorganic base, described organic base includes triethylamine, diisopropylethylamine, pyridine, 4- (N, N- dimethylamino) pyridine, N-methylmorpholine, 2,6- lutidines, one of Isosorbide-5-Nitrae-diazabicyclo [2.2.2] octane and 1,8- diazabicyclo [5.4.0] 11 carbon -7- alkene (DBU)；Described inorganic base includes sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, one of sodium bicarbonate.
The present invention also provides and applies in preparation prevention or treatment atheromatosiss, myocardial infarction, apoplexy, ischemic cerebral thrombosiss, peripheral arterial disease, acute coronary syndrome or the postoperative thrombotic medicine of calcification score containing clopidogrel derivant of the present invention or its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer.
The present invention also provides the pharmaceutical composition containing clopidogrel derivant of the present invention or its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer, and it includes the clopidogrel derivant of the present invention of clinical effective dose or its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer and optional pharmaceutically acceptable carrier.The clopidogrel derivant that the present invention is obtained or its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer can be with independent or administrations in the form of drug regimen.Drug regimen of the present invention can be made into various suitable dosage forms according to route of administration.Using one or more physiologically acceptable carrier, comprise excipient and auxiliary agent, they are conducive to for reactive compound being processed into the preparation that can pharmaceutically use.Suitable dosage form depends on selected route of administration, can be manufactured according to general knowledge well known in the art.
Route of administration can be administered orally, non-bowel or local be administered, preferred oral and injection form administration.The drug-delivery preparation that can be administered orally includes capsule, granule and tablet etc..Patient swallows when having any problem, it would however also be possible to employ Sublingual tablet or other non-mode swallowed are administered.The compounds of this invention can be used for being formulated for parenteral or transdermal administration or transmucosal drug delivery.Or it is administered by the way of suppository or implants.It will be understood by those skilled in the art that the compounds of this invention can adopt suitable drug delivery system to obtain more favourable effect.
Additionally need and point out, the compounds of this invention using dosage and using method depend on factors, including the age of patient, body weight, sex, health status, nutriture, the activity intensity of compound, use time, metabolic rate, the order of severity of disease and diagnosis and treatment doctor subjective judgment.Preferably using dosage is between 2～120mg/kg；The dosage of best 24 hours is per kilogram 20～80mg, and several times administering mode may also be employed.
With reference to embodiment, the present invention is described in further detail, it should be understood that the non-scope being only limitted to these embodiments of the scope of the present invention.
Embodiment 1 ：5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -2- base 2,6-diaminocaproic acid（Compound 1-1）Synthesis
Under water bath condition, Nα- tertbutyloxycarbonyl-Nε- tertbutyloxycarbonyl -1B (22mmol, 7.6g), N, N '-dicyclohexylcarbodiimide (4.4mmol, 0.91g), 4- dimethylamino pyridine (2.2mmol, 0.3g), with anhydrous methylene chloride (30ml) stirring and dissolving.It is subsequently added (S)-(the chloro- phenyl of 2-)-(2- hydroxyl -6,7- dihydro -4H- thiophene [3,2-c] pyridine -5- base)-methyl acetate (26mmol, 8.76g), stirring at normal temperature is overnight.Solids removed by filtration insoluble matter, filtrate solvent evaporated；Add diethyl ether in residue, be filtered to remove the insoluble impurity in solution.Filtrate concentrates, and crosses post with ether for developing solvent is quick, collects product frac.Concentrating under reduced pressure obtains product 6.5g；Compound 1 yield 74.2%.
ESI-MS m/z：465（M+1）+
Embodiment 2 ：5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -2- base 2,6-diaminocaproic acid（Compound 1-2）Synthesis
Synthetic method reference implementation example 1, uses Nα- tertbutyloxycarbonyl-Nε- tertbutyloxycarbonyl-D-Lys replace Nα- tertbutyloxycarbonyl-Nε- tertbutyloxycarbonyl -1B.Obtain compound 1-2, yield 72.1%.
ESI-MS m/z：465（M+1）+
Embodiment 3 ：5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -2- base 2,6-diaminocaproic acid（Compound 1-3）Synthesis
Synthetic method reference implementation example 1, uses Nα- tertbutyloxycarbonyl-Nε- tertbutyloxycarbonyl-DL-Lys replace Nα- tertbutyloxycarbonyl-Nε- tertbutyloxycarbonyl -1B.Obtain compound 1-3, yield 70.1%.
ESI-MS m/z：465（M+1）+
Embodiment 4 ：5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -2 base -2- amino -5- guanidinopentanoic acid（Compound 2-1）Synthesis
Under water bath condition, Nα- tertbutyloxycarbonyl-L-Arginine hydrochlorate (22mmol, 7.23g), N, N '-dicyclohexylcarbodiimide (4.4mmol, 0.91g), 4- dimethylamino pyridine (2.2mmol, 0.3g), with anhydrous methylene chloride (30ml) stirring and dissolving.It is subsequently added (S)-(the chloro- phenyl of 2-)-(2- hydroxyl -6,7- dihydro -4H- thiophene [3,2-c] pyridine -5- base)-methyl acetate (26mmol, 8.76g), stirring at normal temperature is overnight.Solids removed by filtration insoluble matter, filtrate solvent evaporated；Add diethyl ether in residue, be filtered to remove the insoluble impurity in solution.Filtrate concentrates, and crosses post with ether for developing solvent is quick, collects product frac.Concentrating under reduced pressure obtains product 6.1g；Compound 2 yield 69.6%.
ESI-MS m/z：493（M+1）+
Embodiment 5 ：5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -2- base 2- amino -3-（1H- Imidazopyridine -2- base）Ethyl propionate（Compound 3-1）Synthesis
Under water bath condition, Nα- tertbutyloxycarbonyl-Nim- trityl-L-histidine (22mmol, 7.6g), N, N '-dicyclohexylcarbodiimide (4.4mmol, 0.91g), 4- dimethylamino pyridine (2.2mmol, 0.3g), with anhydrous methylene chloride (30ml) stirring and dissolving.It is subsequently added (S)-(the chloro- phenyl of 2-)-(2- hydroxyl -6,7- dihydro -4H- thiophene [3,2-c] pyridine -5- base)-methyl acetate (26mmol, 8.76g), stirring at normal temperature is overnight.Solids removed by filtration insoluble matter, filtrate solvent evaporated；Add diethyl ether in residue, be filtered to remove the insoluble impurity in solution.Filtrate concentrates, and crosses post with ether for developing solvent is quick, collects product frac.Concentrating under reduced pressure obtains product 6.4g；Compound 3 yield 73.1%.
ESI-MS m/z：474（M+1）+
Embodiment 6 ：5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -2 base -2- aminovaleric acid（Compound 4-1）Synthesis
Under water bath condition,, N- tertbutyloxycarbonyl-N'- (2- benzyloxycarbonylchloride base)-L-Orn (22mmol, 7.5g), N, N '-dicyclohexylcarbodiimide (4.4mmol, 0.91g), 4- dimethylamino pyridine (2.2mmol, 0.3g), with anhydrous methylene chloride (30ml) stirring and dissolving.It is subsequently added (S)-(the chloro- phenyl of 2-)-(2- hydroxyl -6,7- dihydro -4H- thiophene [3,2-c] pyridine -5- base)-methyl acetate (26mmol, 8.76g), stirring at normal temperature is overnight.Solids removed by filtration insoluble matter, filtrate solvent evaporated；Add diethyl ether in residue, be filtered to remove the insoluble impurity in solution.Filtrate concentrates, and crosses post with ether for developing solvent is quick, collects product frac.Concentrating under reduced pressure obtains product 6.3g；Compound 4 yield 71.9%.
ESI-MS m/z：451（M+1）+
Embodiment 7 ：5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -2 bases-glycine（Compound 5）Synthesis
Under water bath condition, Nα- tertbutyloxycarbonyl-glycine (22mmol, 7.23g), N, N '-dicyclohexylcarbodiimide (4.4mmol, 0.91g), 4- dimethylamino pyridine (2.2mmol, 0.3g), with anhydrous methylene chloride (30ml) stirring and dissolving.It is subsequently added (S)-(the chloro- phenyl of 2-)-(2- hydroxyl -6,7- dihydro -4H- thiophene [3,2-c] pyridine -5- base)-methyl acetate (26mmol, 8.76g), stirring at normal temperature is overnight.Solids removed by filtration insoluble matter, filtrate solvent evaporated；Add diethyl ether in residue, be filtered to remove the insoluble impurity in solution.Filtrate concentrates, and crosses post with ether for developing solvent is quick, collects product frac.Concentrating under reduced pressure obtains product 6.6g；Compound 5 yield 75.3%.
ESI-MS m/z：394（M+1）+
Embodiment 8 ：5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -4- ketobutyric acid（Compound 6）Synthesis
(S)-(the chloro- phenyl of 2-)-(2- hydroxyl -6,7- dihydro -4H- thiophene [3,2-c] pyridine -5- base)-methyl acetate (6.74g, 20mmol), succinic anhydride (2.4g, 24mmol) sequentially add in toluene (100mL), be subsequently adding 4- (N, N- dimethylamino) pyridine（1.22g, 10mmol) reaction mixture stirs 8 hours, decompression removal solvent at 70～90 DEG C, and be concentrated to dryness residue by HPLC separation（TFA）System, obtains product 3.8g；Compound 7 yield 66.6%.
ESI-MS m/z：437（M+1）+
Comparing embodiment 1 ：FormulaThe preparation of compound（CN 103665042 A）
CN 103665042 A
Preparation method：At 0 DEG C and N2Lower it is added dropwise over compound 7 (5.3g, 36.8mmol) in the agitating solution in anhydrous DCM (100ml) to compound 6 (10g, 29.6mmol) and TEA (12g, 118.4mmol).Then this mixture is stirred at room temperature 12 hours, reaction is quenched with water.Use NaHCO3Solution and salt water washing organic layer, through anhydrous Na2SO4It is dried, be concentrated to dryness.With silicagel column with (PE:EA=30:1-1:1) purification residue, obtains compound 8 (4.7g, 47.0%), is white solid.
In room temperature and N2Lower add TMSBr (15.4mg, 101mmol) in the solution in anhydrous DCM (100mL) to compound 8 (4.5g, 10.1mmol).Then stir this mixture 2 hours, remove solvent under reduced pressure.Residue is re-dissolved in methanol, is concentrated to dryness.This residue separates (TFA) system by HPLC, obtains Formula V compound (1.3g, 28.9%), is white solid
ESI-MS m/z：417（M+1）+
Comparing embodiment 2 ：FormulaThe preparation of compound（CN 103665042 A）
CN 103665042 A
Preparation method：At -78 DEG C and N2Lower to compound 6 (19.2g, 56.4mmol）With NaI (17.2g, 112.8mmol) in the agitating solution in anhydrous THF (120mL), it is added dropwise over LHMDS (169.2mL, 1.0M in THF, 2.85mmol), then this mixture is stirred at room temperature 30 minutes, add compound 9 (21.6g, 84.4mmol) afterwards, be stirred for 10 hours.Use NH4Cl solution is quenched reaction, is extracted with EA.Use NaHCO3Solution and salt water washing organic layer, through anhydrous Na2SO4It is dried, be concentrated to dryness.With silicagel column with (PE:EA=50:1-3:1) purification residue, obtains compound 10 (2.3mg, 11.2%), is white solid.
Add TFA (30mL) to compound 10 (9g, 16.1mmol) at 0 DEG C in the solution in anhydrous DCM (50mL).Then stir this mixture 30 minutes, remove dissolving under reduced pressure, and be concentrated to dryness.Residue is separated (TFA) system by HPLC, obtains Formula IV compound (1.7g, 18.8%), be white solid.
ESI-MS m/z：447（M+1）+
Test example 1:The compounds of this invention (compound 1-1, compound 2-1, compound 3-1, compound 4-1, compound 5, compound 6) and comparing embodiment compound（FormulaCompound, formulaCompound）Stability contrast test
Take compound 1-1, compound 2-1, compound 3-1, compound 4-1, compound 5, compound 6, formulaCompound, formulaCompound, simulation listing packaging, places, respectively in 1st month, the 2nd month, the 3rd month and separately sampled detection in 6th month under the conditions of 40 ± 2 DEG C of temperature, relative humidity 75 ± 5% for a long time, testing result and the detection data of 0 month are compared, and result see table.
Result following table shows, succinic acid derivative（Compound 6）Stability be slightly worse than amino acid derivativges（Compound 1-1, compound 2-1, compound 3-1, compound 4-1, compound 5）；But the compound stability of the present invention, the discloseder formula all than beforeCompound, formulaStability of compounds.Due to its outstanding stability make its do not need in long term storage harshness storage requirement it is easy to produce enforcement.
Embodiment 2 ：Platelet aggregation inhibitory activity is tested
Medicine and preparation：Positive drug is clopidogrel sulfate.Positive drug and test-compound are made into suspension with 0.5%CMC-Na (sodium carboxymethyl cellulose) and supply animal administrable.
0.5% carboxymethyl cellulose, China Medicine (Group) Shanghai Chemical Reagent Co.,.
ADP, Sigma, the U.S..
Animal：Wistar rat, 200-250g, male, Jiangning county Qinglongshan animal reproduction field.
Instrument：Platelet aggregation instrument (560Ca), CHRONO-LOG, the U.S.
Method：Reference BORN turbidimetry (Nature, 1962,194 (4832)：927), the compounds of this invention (above-described embodiment preparation) is carried out with the pharmacological activity test of antiplatelet aggregation.To rich in adding coagulant polymers adenosine diphosphate (ADP) (ADP) stirring in hematoblastic blood plasma (PRP), make platelet aggregation.Hematoblastic gathering causes the change of optical density, can be detected by spectrophotometer.This experiment can be evaluated test-compound and be administered the platelet aggregation causing in vivo or in vitro.
Platelet aggregation inhibitory activity is tested：By rat random packet, gastric infusion test-compound (is suspended using front using 0.5% carboxymethyl cellulose), and dosage is 3mg/kg, and the oral gavage of blank control group gives 0.5% CMC-Na of same volume.After 2h, abdominal aortic blood (pentobarbital sodium intraperitoneal injection of anesthesia), 3.8% sodium citrate anticoagulant, whole blood is that 9: 1,1000rpm is centrifuged 7min with the ratio of anticoagulant, prepares platelet rich plasma (PRP).PRP is adjusted with platelet poor plasma (PPP), makes platelet count be maintained at 2 × 106/ml.PRP is taken to add in test cup, 37 DEG C of incubation 10min, with PRP zeroing, PPP adjusts 100%, with ADP (final concentration of 5 μM) as derivant, measure platelet aggregation percent by turbidimetry with platelet aggregation instrument, statistics are carried out with t- inspection and compares.Platelet aggregation inhibition rate is calculated as follows：
Platelet aggregation inhibition rate (%)=[1- (delivery tube is assembled percentage rate/control tube and assembled percentage rate)] × 100%.
Result following table shows, test-compound has anti-platelet aggregation function, and wherein its Oral availability significantly improves than clopidogrel；When oral, the present invention provides the platelet aggregation suppression function of compound to be significantly better than clopidogrel, or similar with clopidogrel.And, test-compound is precursor compound, the enzymatic activity being against CYP2C19 is disobeyed in its metabolism in vivo, therefore can solve the problems, such as clopidogrel Resistant；There is good DEVELOPMENT PROSPECT.
| Medicine | Size of animal | Maximum agglutination rate |
| Compound 1 | 6 | 17.89 |
| Compound 2 | 6 | 23.73 |
| Compound 3 | 6 | 24.65 |
| Compound 4 | 6 | 22.00 |
| Compound 5 | 6 | 30.65 |
| Compound 6 | 6 | 20.02 |
| Clopidogrel | 6 | 60.33 |
| CMC | 6 | 75.45 |
Test example 3:Pharmacokinetic Evaluation
To the compounds of this invention (above-described embodiment preparation) and comparing embodiment compound（Prepared by comparing embodiment）Carry out internal Pharmacokinetic Evaluation.
Method：
By the compounds of this invention (above-described embodiment preparation) and comparing embodiment compound（Prepared by comparing embodiment）It is dissolved in blank solution (30%PEG-400) with the concentration of 10g/L respectively.
Laboratory animal is male mice, 6 to 8 week old, and body weight 190-215 gram, purchased from purchased from Jiangning county Qinglongshan animal reproduction field.It is randomly divided into 8 groups based on Mouse Weight, every group of 3 animals.The dosage of each group mice and approach see table.
Before pharmacokinetic trial, by mice fasting 16 hours.Then according to (15mg/kg) is administered the compound of single dosage by oral administration shown in table.Take the mode timed collection blood 200 μ L upon administration of jugular puncture, wherein for the animal groups through intravenously administrable, 0,15 minutes upon administration, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours collect bloods.By blood sample collection in the sample cell with EDTA, immediately with 4000rpm centrifugation of blood samples 5 minutes at 4 DEG C, then blood plasma is transferred in another sample cell, be stored under -20 degrees Celsius.
Sample is carried out with pharmacokineticss inspection, the method for employing and instrument are as follows：
HPLC ：Dionex U-3000（Thermo company)
System(SerialNO:4353) ；
MS：AB API4000Q Trap LC/MS/MS
instrument(Serial NO.AR19020706)
Pillar：Phenomenex Luna 5μC18(2.0×50mm)
Mobile phase：95% acetonitrile (0.1% formic acid) and 5% acetonitrile (0.1% formic acid)
Quantitative approach：Internal standard method
The compounds of this invention (above-described embodiment preparation) and comparing embodiment compound（Prepared by comparing embodiment）Pharmacokinetic results following table.
NA：Data does not obtain.
Result following table shows, succinic acid derivative（Compound 6）Half-life be slightly worse than amino acid derivativges（Compound 1-1, compound 2-1, compound 3-1, compound 4-1, compound 5）；But the Compound half-life of the present invention, the discloseder formula all than beforeCompound, formulaThe half-life of compound significantly extends.Bioavailability ratioCompound improves 2～3 times, and wherein, the half-life of compound 5 is up to 15.7 hours, and Fig. 1 is shown in by its pharmacokineticss collection of illustrative plates.
Claims (10)
1. the clopidogrel derivant shown in formula (I) or its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer,
Wherein：
R1It is hydrogen atom, halogen, cyano group, alkyl, haloalkyl, hydroxyalkyl, carboxyl or carboxylic acid ester groups；
M is 0 or 2；
N is 0 to 8 integer；
R2Or R3It is independently hydrogen or C1-C6Alkyl or optionally substituted C1-C6Alkyl；And
R4ForOr succinic acid
,
Wherein R5For amino acid side groups, described aminoacid is selected from：Lysine, arginine, histidine, ornithine, 2,3- diaminopropionic acid, 2,4- diaminopropionic acid, alanine, L-Valine, leucine, isoleucine, Phenylalanine, tryptophan, Methionine, glycine, serine, threonine, cysteine, tyrosine, agedoite, L-Glutamine, aspartic acid, glutamic acid.
2. aminoacid according to claim 1 can be D type, L-type and DL type.
3. the compound of formula (I) pharmaceutically acceptable salt or hydrate according to claim 1.
4. the clopidogrel derivant according to claim 1 or its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer are it is characterised in that described clopidogrel derivant is as shown in Formula II：
Wherein, group R1、R2、R3、R4And m and n such as claim 1 is defined.
5. the clopidogrel derivant according to claim 1,3,4 or its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer are it is characterised in that R1For Cl；R4ForOr succinic acid,
M is 1；N is 0；Wherein R5For amino acid side groups, described aminoacid is selected from：Lysine, arginine, histidine, ornithine, glycine.
6. clopidogrel derivant according to any one of claim 1 to 5 or its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer are it is characterised in that described clopidogrel derivant includes following compounds；
5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -2- base 2,6-diaminocaproic acid（Compound 1）
Compound 1-1
Compound 1-2
Compound 1-3
5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -2 base -2- amino -5- guanidinopentanoic acid（Compound 2）
Compound 2-1
Compound 2-2
Compound 2-3
5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -2- base 2- amino -3-（1H- Imidazopyridine -2- base）Ethyl propionate（Compound 3）
Compound 3-1
Compound 3-2
Compound 3-3
5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -2 base -2- aminovaleric acid（Compound 4）
Compound 4-1
Compound 4-2
Compound 4-3
5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -2 bases-glycine（Compound 5）
Compound 5
5-（（S）-（Methoxycarbonyl group）（2- chlorphenyl）Methyl）- 4,5,6,7- Tetramethylene sulfide simultaneously [3,2-c] pyridine -4- ketobutyric acid（Compound 6）
Compound 6
.
7. the pharmaceutical composition containing the clopidogrel derivant described in claim 1 or its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer.
8. pharmaceutical composition according to claim 7 is it is characterised in that wherein contain one or more pharmaceutically acceptable carriers.
9. purposes in the medicine preparing thrombosis and thromboembolism relevant disease for the clopidogrel derivant or its pharmaceutical salts, solvated compoundses, racemic mixture or enantiomer or the pharmaceutical composition according to claim 7 to 8 according to any one of claim 1,3,4,5,6.
10. pharmaceutical composition according to claim 7, for preventing or treating atheromatosiss, myocardial infarction, apoplexy, ischemic cerebral thrombosiss, peripheral arterial disease, acute coronary syndrome or the postoperative thrombosiss of calcification score.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2669348C1 (en) * | 2017-11-15 | 2018-10-10 | Федеральное государственное автономное образовательное учреждение высшего образования "Белгородский государственный национальный исследовательский университет" (НИУ "БелГУ") | Method for inhibiting nuclear kappa b factor with using 2-ethyl-6-methyl-3-hydroxipiridinium l-2,6-diaminohexanoate in culture of cells |
| CN111166745A (en) * | 2020-01-19 | 2020-05-19 | 成都施贝康生物医药科技有限公司 | Composition containing racemic oxypyramine or salt thereof and application |
| 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 |
| WO2024087673A1 (en) * | 2022-10-26 | 2024-05-02 | 中国科学院大学 | Antiplatelet drug and preparation method, and antiplatelet drug capture agent |
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| CN102002053A (en) * | 2009-09-02 | 2011-04-06 | 陕西合成药业有限公司 | Tetrahydro thienopyridine derivative for treating |
| 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 |
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| CN102002053A (en) * | 2009-09-02 | 2011-04-06 | 陕西合成药业有限公司 | Tetrahydro thienopyridine derivative for treating |
| 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 |
| CN102993210A (en) * | 2012-12-19 | 2013-03-27 | 苏春华 | New thienopyridine compound |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2669348C1 (en) * | 2017-11-15 | 2018-10-10 | Федеральное государственное автономное образовательное учреждение высшего образования "Белгородский государственный национальный исследовательский университет" (НИУ "БелГУ") | Method for inhibiting nuclear kappa b factor with using 2-ethyl-6-methyl-3-hydroxipiridinium l-2,6-diaminohexanoate in culture of cells |
| CN111166745A (en) * | 2020-01-19 | 2020-05-19 | 成都施贝康生物医药科技有限公司 | Composition containing racemic oxypyramine or salt thereof and application |
| 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 |
| WO2024087673A1 (en) * | 2022-10-26 | 2024-05-02 | 中国科学院大学 | Antiplatelet drug and preparation method, and antiplatelet drug capture agent |
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