CN105153192B - Substituted tetrahydro thienopyridine derivative and its application - Google Patents
Substituted tetrahydro thienopyridine derivative and its application Download PDFInfo
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- CN105153192B CN105153192B CN201510553507.4A CN201510553507A CN105153192B CN 105153192 B CN105153192 B CN 105153192B CN 201510553507 A CN201510553507 A CN 201510553507A CN 105153192 B CN105153192 B CN 105153192B
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- clopidogrel
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- acid
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- WJFYLCXWEXZNHU-UHFFFAOYSA-N 2,3,3a,4-tetrahydrothieno[3,2-b]pyridine Chemical class N1C=CC=C2SCCC21 WJFYLCXWEXZNHU-UHFFFAOYSA-N 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 16
- 239000002253 acid Substances 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 229940079593 drug Drugs 0.000 claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 8
- 208000005189 Embolism Diseases 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 230000002265 prevention Effects 0.000 claims abstract description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 210000004369 blood Anatomy 0.000 claims description 7
- 239000008280 blood Substances 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 229910052731 fluorine Chemical group 0.000 claims description 5
- 239000011737 fluorine Chemical group 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 206010002383 Angina Pectoris Diseases 0.000 claims description 2
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
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- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 239000012453 solvate Substances 0.000 abstract description 8
- 238000010189 synthetic method Methods 0.000 abstract 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 48
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- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 32
- -1 Methoxyl group Chemical group 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 19
- 238000012360 testing method Methods 0.000 description 18
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
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- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 7
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- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 5
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- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical group CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
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- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 4
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 4
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 4
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
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- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
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- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- ARBOVOVUTSQWSS-UHFFFAOYSA-N hexadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCC(Cl)=O ARBOVOVUTSQWSS-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- FDEODCTUSIWGLK-UHFFFAOYSA-N hydrogen sulfate;hydron;methyl 2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetate Chemical compound OS(O)(=O)=O.C1CC=2SC=CC=2CN1C(C(=O)OC)C1=CC=CC=C1Cl FDEODCTUSIWGLK-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 150000007529 inorganic bases Chemical group 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 229910052740 iodine Chemical group 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000001419 myristoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229950009730 pentafluranol Drugs 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229960004197 prasugrel Drugs 0.000 description 1
- DTGLZDAWLRGWQN-UHFFFAOYSA-N prasugrel Chemical compound C1CC=2SC(OC(=O)C)=CC=2CN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 DTGLZDAWLRGWQN-UHFFFAOYSA-N 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical class C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
-
- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of substituted tetrahydro thienopyridine derivative and its application, as shown in logical formula (I), pharmaceutically acceptable acid salt, solvate or hydrate, wherein R1、R2It is defined with X such as specification.In addition, the invention also discloses the synthetic method of the compound, pharmaceutical composition and they preparation for inhibit platelet aggregation, prevention or treatment thrombus and embolism related disease drug in purposes.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, simultaneously more specifically to a kind of novel substituted thiophane
Pyridine derivate, pharmaceutically acceptable acid salt, solvate or hydrate, their preparation method, pharmaceutical composition and it
Preparation for inhibit platelet aggregation, prevention or treatment thrombus and embolism related disease drug in purposes.
Background technique
Clopidogrel is clinically widely applied medicament for resisting platelet aggregation, in the research of its internal metabolic process,
It was found that there is 85% clopidogrel proto-drug to be metabolized as inactive clopidogrel carboxylic acid derivates through liver hydrolysis；In addition,
The clopidogrel for not being metabolized as nonactive metabolite also needs to rely on P450 enzyme system metabolism activation, due to Different Individual liver
The difference of interior P450 enzyme system expression so that rely on the clopidogrel that the metabolism of P450 enzyme system works generated on clinical therapeutic efficacy compared with
Big individual difference, the weak individual of P450 metabolic activity, it is inefficient or invalid to take clopidogrel, and it is existing to generate " clopidogrel Resistant "
, the cardiovascular events such as thrombosis incidence cannot reduce.
Prasugrel is that another antiplatelet of drugmaker and the exploitation of Lilly drugmaker is poly- altogether for Japan three
Collect drug, it is rapid-action, active strong although " drug resistance " not similar compared with clopidogrel, there is bigger bleeding wind
Danger.
So rapid-action, active strong, without drug resistance, while the small medicament for resisting platelet aggregation of bleeding risk becomes
Clinical urgent need.
Summary of the invention
The present invention provides a kind of novel substituted tetrahydro thienopyridine derivatives, as platelet aggregation inhibitor
Development in object, prevention or treatment thrombus and embolism related disease；These drugs have it is rapid-action, active it is strong, bleeding risk is small
And difference between bion it is small the features such as.
The object of the present invention is to provide a kind of novel substituted tetrahydro thienopyridine derivatives, it passes through in blood
Esterase (rather than relying on P450 enzyme system in liver) metabolism generates active metabolite identical with clopidogrel.Because esterase is in people
It is generally existing in body blood, avoid " clopidogrel Resistant " phenomenon of clopidogrel.
A second object of the present invention is to provide the preparation methods of above-mentioned tetrahydro thienopyridine derivative.
Third object of the present invention is to provide the pharmaceutical compositions comprising above-mentioned tetrahydro thienopyridine derivative.
Fourth object of the present invention is to provide above-mentioned tetrahydro thienopyridine derivative or pharmaceutical composition and uses in preparation
Purposes in inhibition platelet aggregation, or prevention or treatment thrombus and the drug of embolism related disease.
Specifically, the present invention provides a kind of substituted tetrahydro thienopyridine derivative, such as compounds of formula I,
Or its pharmaceutically acceptable acid salt, solvate or hydrate:
Wherein:
R1Linear or branched alkyl group, the naphthenic base or OR of 3-6 carbon for 1-6 carbon3；
R2ForTauryl-, stearyl, palmityl, lauroyl, myristoyl
Base, oleoyl, sub-oleoyl or linolenyl；
R3For the linear or branched alkyl group of 1-6 carbon or the naphthenic base of 3-6 carbon；
R4For the naphthenic base of hydrogen, the linear or branched alkyl group of 1-6 carbon or 3-6 carbon；With
X is hydrogen, chlorine, fluorine, bromine or iodine；
N=0-6.
In a kind of preferred embodiment of the invention, compound of formula I provided by the invention, wherein R1For cyclopropyl or
Methoxyl group or ethyoxyl.
In a kind of preferred embodiment of the invention, compound of formula I provided by the invention, wherein R2For
R4For the naphthenic base of hydrogen, the linear or branched alkyl group of 1-6 carbon or 3-6 carbon；N=0-6.
In a kind of preferred embodiment of the invention, compound of formula I provided by the invention, wherein X is chlorine or fluorine.
In a kind of preferred embodiment of the invention, compound of formula I provided by the invention, wherein R1For cyclopropyl or
Methoxyl group, ethyoxyl；
R2For
R4For the naphthenic base of hydrogen, the linear or branched alkyl group of 1-6 carbon or 3-6 carbon；N=0-6；With
X is chlorine or fluorine.
In a kind of more preferred of the invention, compound of formula I provided by the invention, wherein R1For methoxyl group；
R2For
R4For the naphthenic base of hydrogen, the linear or branched alkyl group of 1-6 carbon or 3-6 carbon；N=0-6；With
X is chlorine.
In a kind of preferred embodiment of the invention, compound of formula I provided by the invention, wherein R2For tauryl-,
Stearyl, palmityl, lauroyl, cardamom acyl group, oleoyl, sub-oleoyl or linolenyl.
In a kind of preferred embodiment of the invention, compound of formula I provided by the invention, wherein R1For cyclopropyl or
Methoxyl group or ethyoxyl；
R2For tauryl-, stearyl, palmityl, lauroyl, cardamom acyl group, oleoyl, sub-oleoyl or Asia
Numb acyl group；With
X is chlorine or fluorine.
In a kind of more preferred of the invention, compound of formula I provided by the invention, wherein R1For methoxyl group；
R2For tauryl-, stearyl, palmityl, lauroyl, cardamom acyl group, oleoyl, sub-oleoyl or Asia
Numb acyl group；With
X is chlorine.
In particularly preferred embodiment of the invention, compound provided by the invention in following compound one
Kind or its pharmaceutically acceptable acid salt, solvate or hydrate:
In embodiments of the invention, the derivative provided by the invention includes the enantiomter of compound of formula I
And racemic modification.
In embodiments of the invention, derivative of the present invention includes compound of formula I or its is pharmaceutically acceptable
Acid salt, including but not limited to compound and it is following acid formed salt: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, winestone
Acid, phosphoric acid, lactic acid, acetic acid, maleic acid, fumaric acid, malic acid, tussol, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, oxalic acid,
Or succinic acid.
In embodiments of the invention, compound of formula I provided by the invention, wherein the straight chain or branch of the 1-6 carbon
Alkyl group is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, amyl or hexyl.
In embodiments of the invention, compound of formula I provided by the invention, wherein the naphthenic base of the 3-6 carbon is selected
From cyclopropyl alkyl, cyclobutane base, pentamethylene base or cyclohexyl.
Second aspect, the present invention provides above-mentioned substituted-tetrahydro thienopyridine derivative compound of formula I or its pharmaceutically
The preparation method of acceptable acid salt, solvate or hydrate, including the following steps:
Formula II compound is reacted with formula III compound or formula IV compound, obtains compound of formula I
Wherein, the R in Formula II compound, formula III compound and formula IV compound1、R2, X as defined in compound of formula I,
Z is leaving group, such as: chlorine, pentafluranol base, nitro phenolic group.
Embodiment as one preferred, the present invention provides above-mentioned substituted tetrahydro thienopyridine derivative Formulas I
The preparation method of compound or its pharmaceutical acceptable acid formula salt, solvate or hydrate, the method includes by Formula II
It closes object or its salt is dissolved in organic solvent, alkali is added portionwise under cooling, is then reacted with formula III compound, obtains Formulas I chemical combination
Object can be further purified such as recrystallizing, column chromatographs by conventional method if necessary.Here, the alkali can be with
It is inorganic base or organic base, can be selected from sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus, triethylamine or N, N- diisopropyl
Ethamine etc..
Particularly, the compound that the ends such as the compounds of this invention such as MJ10605 are contained with reactive group, can be used phase
The protecting group answered and after at ester condensation reaction, increases if 9-fluorenylmethyloxycarbonyl is protected and uses piperidines deprotection steps.
The third aspect, the present invention also provides the aforementioned substituted-tetrahydro thienopyridine derivatives comprising therapeutically effective amount to include
The pharmaceutical composition of compound of formula I or its acid salt pharmaceutically received, solvate or hydrate, the pharmaceutical composition
It can also include pharmaceutical acceptable carrier or diluent.The pharmaceutical composition can by intravenous injection administration, by be injected into tissue to
Medicine, Intraperitoneal medication, oral administration or intranasal administration.The pharmaceutical composition can have selected from solution, dispersion, suspension,
The form of powder, capsule, tablet, pill, time-release capsules, time release tablet and time release pill.The pharmaceutical composition
The dosage of object is 5-5000mg/ days.
Fourth aspect, the present invention provides above-mentioned substituted-tetrahydro thienopyridine derivative such as compound of formula I or its pharmacy
Acid salt, solvate or the hydrate of upper receiving are in preparation for platelet aggregation-against, prevention or treatment thrombus and embolism
Related disease, especially prevent or treat atherosclerosis disease, myocardial infarction, angina pectoris, apoplexy, ischemic cerebral thrombosis,
Purposes in the drug of peripheral arterial disease, acute coronary artery syndrome or the postoperative thrombosis of calcification score.
Compared with prior art, novel substituted tetrahydro thienopyridine derivative of the invention has significant inhibit
Platelet aggregation, antiplatelet aggregative activity are even significantly better than clopidogrel.
The compound of the present invention is generated and chlorine pyrrole by esterase (rather than relying on P450 enzyme system in liver) metabolism in blood
The identical active metabolite of Gray avoids " clopidogrel Resistant " phenomenon of clopidogrel.
In addition, release experiment shows that new substituted tetrahydro thienopyridine derivative of the invention can have in vivo in vivo
It is converted into pharmacological activity metabolin and plays a role to effect, and precursor 2- oxygroup-clopidogrel concentration of active metabolite is significant
Higher than clopidogrel.
Detailed description of the invention
2- oxygen after the compounds of this invention and bisulfate clopidogrel of 2mg/kg is given in Fig. 1 male SD rat (n=3) stomach-filling
Base-clopidogrel blood concentration (ng/mL).
L-Arginine compares (20 μm of ol/L ADP inductions) after administration in Fig. 2 male SD rat continuous 5 days.
Specific embodiment
Carry out exemplary illustration embodiment of the present invention by the following examples, for those of ordinary skill in the art and
Speech still falls within guarantor of the invention to the improvement that embodiment of the present invention carries out according to the prior art under the teachings of the present invention
It protects in range.
The source of raw materials of compound used in embodiment is: all reagents are bought by Reagent Company, starting material
(2S) -2- (2- chlorphenyl) -2- (2- oxygen -5,6,7,7a- thiophane simultaneously [3,2-c] pyridyl group) methyl acetate with reference to China specially
The method of benefit application 201210333184.4 is synthesized by the benzene sulfonate of 2- chloro mandelic acid methyl esters and is obtained through splitting.
Hydrogen nuclear magnetic resonance modal data is acquired and is handled by Bruker AV-300 nuclear magnetic resonance chemical analyser.
Embodiment 1
The synthesis of cyclohexyloxy
60% sodium hydride (8.79g) is suspended in tetrahydrofuran (500ml), is added cyclohexanol (10g), mixture exists
It is stirred at 0 DEG C 30 minutes, bromoacetic acid (13.9g) then is added, adds rear back flow reaction 2 hours.Water is added into reaction solution, revolves
Turn evaporimeter removal organic solvent, aqueous solution is diluted with water to 200ml, is washed with methyl tertiary butyl ether(MTBE), with 1N hydrochloric acid acidifying water
Layer, is extracted with methyl tertiary butyl ether(MTBE), separates organic layer, and anhydrous magnesium sulfate is dry, is evaporated off under reduced pressure organic solvent, obtains grease
(cyclohexyloxy) (12.9g), yield 81.6%.1H-NMR(CDCl3) δ: 1.18~1.47 (5H, m), 1.52~1.63
(1H, m), 1.72~1.85 (2H, m), 1.90~2.03 (2H, m), 3.36~3.47 (1H, m), 4.13 (2H, s).
Embodiment 2
The synthesis of MJ10601
Cyclohexyloxy (1.58g) is suspended with 10ml thionyl chloride, and 60 DEG C are reacted 2 hours, and evaporating solvent under reduced pressure obtains ring
Hexyloxy chloroacetic chloride；By (2S) -2- (2- chlorphenyl) -2- (2- oxygen -5,6,7,7a- thiophane simultaneously [3,2-c] pyridyl group) second
Sour methyl esters (0.3g) is dissolved in NMP (N-Methyl pyrrolidone) (10ml), and 0.3ml triethylamine is added, cyclohexyloxy is added dropwise at 0 DEG C
Chloroacetic chloride (0.18g) after completion of dropwise addition, is warming up to room temperature reaction 3 hours, reaction solution is poured into 30ml water, ethyl acetate
(30ml × 3) aqueous phase extracted merges organic phase, is washed with saturated sodium bicarbonate aqueous solution, with saturated common salt water washing, anhydrous sulphur
Sour sodium is dry, is evaporated organic phase and obtains grease 0.7g.Using the isolated white solid 0.25g of silica gel column chromatography, yield
52.3%.MS (m/z): 478.2 [M+1]+；1H-NMR (DMSO-d6) δ: 1.16~1.43 (5H, m), 1.51~1.63 (1H,
M), 1.72~1.86 (2H, m), 1.89~2.05 (2H, m), 2.66~2.91 (m, 4H), 3.35~3.69 (m, 3H), 3.71
(s, 3H), 4.14 (2H, s), 4.91 (s, 1H), 6.25 (s, 1H), 7.21~7.68 (m, 4H).
Embodiment 3
The synthesis of propoxyl group acetic acid
60% sodium hydride (8.79g) is suspended in tetrahydrofuran (500ml), is added normal propyl alcohol (6g), mixture is 0
It is stirred at DEG C 30 minutes, bromoacetic acid (13.9g) then is added, adds rear back flow reaction 2 hours.Water is added into reaction solution, revolves
Turn evaporimeter removal organic solvent, aqueous solution is diluted with water to 200ml, is washed with methyl tertiary butyl ether(MTBE), with 1N hydrochloric acid acidifying water
Layer, is extracted with methyl tertiary butyl ether(MTBE), separates organic layer, and anhydrous magnesium sulfate is dry, is evaporated off under reduced pressure organic solvent, obtains grease
(propoxyl group acetic acid) (10.9g), yield 92.3%.1H-NMR(CDCl3) δ: 0.89 (3H, t), 1.51 (2H, m), 3.37 (2H,
t),4.12(2H,s)。
Embodiment 4
The synthesis of MJ10602
Propoxyl group acetic acid (1.18g) is suspended with 10ml thionyl chloride, and 60 DEG C are reacted 2 hours, and evaporating solvent under reduced pressure obtains the third oxygen
Base chloroacetic chloride；By (2S) -2- (2- chlorphenyl) -2- (2- oxygen -5,6,7,7a- thiophane simultaneously [3,2-c] pyridyl group) acetic acid first
Ester (0.3g) is dissolved in NMP (N-Methyl pyrrolidone) (10ml), and 0.3ml triethylamine is added, and propoxyl group chloroacetic chloride is added dropwise at 0 DEG C
(0.14g) after completion of dropwise addition, is warming up to room temperature reaction 3 hours, reaction solution is poured into 30ml water, ethyl acetate (30ml × 3)
Aqueous phase extracted merges organic phase, is washed with saturated sodium bicarbonate aqueous solution, and with saturated common salt water washing, anhydrous sodium sulfate is dry,
It is evaporated organic phase and obtains grease 0.8g.Using the isolated white solid 0.21g of silica gel column chromatography, yield 47.9%.MS(m/
Z): 438.1 [M+1]+；1H-NMR (DMSO-d6) δ: 0.88 (3H, t), 1.51 (2H, m), 2.65~2.91 (m, 4H), 3.34~
3.68 (m, 4H), 3.71 (s, 3H), 4.13 (2H, s), 4.93 (s, 1H), 6.26 (s, 1H), 7.23~7.68 (m, 4H).
Embodiment 5
The synthesis of 2- (oxinane -4- oxygroup) acetic acid
60% sodium hydride (8.79g) is suspended in tetrahydrofuran (500ml), oxinane -4- alcohol is added
(10.2g), mixture stir 30 minutes at 0 DEG C, bromoacetic acid (13.9g) then are added, adds rear back flow reaction 2 hours.To
Water is added in reaction solution, Rotary Evaporators remove organic solvent, and aqueous solution is diluted with water to 200ml, is washed with methyl tertiary butyl ether(MTBE)
It washs, with 1N hydrochloric acid Acidified aqueous layer, is extracted with methyl tertiary butyl ether(MTBE), separate organic layer, anhydrous magnesium sulfate is dry, has been evaporated off under reduced pressure
Solvent obtains grease (2- (oxinane -4- oxygroup) acetic acid) (10.9g), yield 69.0%.1H-NMR(CDCl3) δ: 1.58
~1.91 (4H, m), 3.23 (1H, m), 3.41~3.65 (4H, m), 4.21 (2H, s).
Embodiment 6
The synthesis of MJ10603
2- (oxinane -4- oxygroup) acetic acid (1.60g) is suspended with 10ml thionyl chloride, and 60 DEG C are reacted 2 hours, and decompression is steamed
Except solvent, 2- (oxinane -4- oxygroup) chloroacetic chloride is obtained；By (2S) -2- (2- chlorphenyl) -2- (2- oxygen -5,6,7,7a- tetrahydro
Thieno [3,2-c] pyridyl group) methyl acetate (0.3g) is dissolved in NMP (N-Methyl pyrrolidone) (10ml), tri- second of 0.3ml is added
2- (oxinane -4- oxygroup) chloroacetic chloride (0.18g) is added dropwise in amine at 0 DEG C, and after completion of dropwise addition, it is small to be warming up to room temperature reaction 3
When, reaction solution is poured into 30ml water, ethyl acetate (30ml × 3) aqueous phase extracted, merges organic phase, use saturated sodium bicarbonate water
Solution washing, with saturated common salt water washing, anhydrous sodium sulfate is dry, is evaporated organic phase and obtains grease 1.1g.Using silica gel column layer
Analyse isolated white solid 0.23g, yield 47.9%.MS (m/z): 480.2 [M+1]+；1H-NMR (DMSO-d6) δ: 1.61~
1.89 (m, 4H), 2.66~2.91 (m, 4H), 3.25 (s, 1H), 3.38~3.75 (m, 6H), 3.71 (s, 3H), 4.21 (s,
2H), 4.96 (s, 1H), 6.23 (s, 1H), 7.22~7.68 (m, 4H).
Embodiment 7
The synthesis of isopropyl ethoxyacetic acid
60% sodium hydride (8.79g) is suspended in tetrahydrofuran (500ml), is added isopropanol (6g), mixture is 0
It is stirred at DEG C 30 minutes, bromoacetic acid (13.9g) then is added, adds rear back flow reaction 2 hours.Water is added into reaction solution, revolves
Turn evaporimeter removal organic solvent, aqueous solution is diluted with water to 200ml, is washed with methyl tertiary butyl ether(MTBE), with 1N hydrochloric acid acidifying water
Layer, is extracted with methyl tertiary butyl ether(MTBE), separates organic layer, and anhydrous magnesium sulfate is dry, is evaporated off under reduced pressure organic solvent, it is different to obtain grease
Propyl ethoxyacetic acid (10.3g), yield 87.3%.1H-NMR(CDCl3) δ: 1.15 (6H, d), 3.21 (1H, m), 4.33 (2H,
s)。
The synthesis of embodiment 8MJ10604
Isopropyl ethoxyacetic acid (1.18g) is suspended with 10ml thionyl chloride, and 60 DEG C are reacted 2 hours, and evaporating solvent under reduced pressure obtains
Isopropyl oxygroup chloroacetic chloride；By (2S) -2- (2- chlorphenyl) -2- (2- oxygen -5,6,7,7a- thiophane simultaneously [3,2-c] pyridine
Base) methyl acetate (0.3g) is dissolved in NMP (N-Methyl pyrrolidone) (10ml), and 0.3ml triethylamine is added, is added dropwise at 0 DEG C different
Propyl oxygroup chloroacetic chloride (0.18g) after completion of dropwise addition, is warming up to room temperature reaction 3 hours, reaction solution is poured into 30ml water, second
Acetoacetic ester (30ml × 3) aqueous phase extracted merges organic phase, is washed with saturated sodium bicarbonate aqueous solution, with saturated common salt water washing,
Anhydrous sodium sulfate is dry, is evaporated organic phase and obtains grease 0.9g.Using the isolated white solid 0.22g of silica gel column chromatography, receive
Rate 49.2%.MS (m/z): 438.2 [M+1]+；1H-NMR (DMSO-d6) δ: 1.14 (d, 6H), 2.63~2.91 (m, 4H), 3.12
(m, 1H), 3.36~3.66 (m, 2H), 3.73 (s, 3H), 4.37 (s, 2H), 4.96 (s, 1H), 6.27 (s, 1H), 7.22~
7.69(m,4H)。
Embodiment 9
The synthesis of MJ10611
By (2S) -2- (2- chlorphenyl) -2- (2- oxygen -5,6,7,7a- thiophane simultaneously [3,2-c] pyridyl group) methyl acetate
(0.3g) is dissolved in NMP (N-Methyl pyrrolidone) (10ml), and 0.3ml triethylamine is added, hexadecanoyl chloride is added dropwise at 0 DEG C
(0.4g) after completion of dropwise addition, is warming up to room temperature reaction 3 hours, reaction solution is poured into 30ml water, ethyl acetate (30ml × 3)
Aqueous phase extracted merges organic phase, is washed with saturated sodium bicarbonate aqueous solution, and with saturated common salt water washing, anhydrous sodium sulfate is dry,
It is evaporated organic phase and obtains grease 1.3g.Using the isolated white solid 0.45g of silica gel column chromatography, yield 43.3%.MS(m/
Z): 576.2 [M+1]+；1H-NMR (DMSO-d6) δ: 0.92 (t, 3H), 1.25~1.32 (m, 24H), 1.53 (m, 2H), 2.53
(t, 2H), 2.67~3.12 (m, 4H), 3.39~3.68 (m, 2H), 3.75 (s, 3H), 4.96 (s, 1H), 6.25 (s, 1H),
7.23~7.68 (m, 4H).
Embodiment 10
The preparation of MJ10601 hydrochloride
Compound MJ10601 (478mg) is dissolved in anhydrous tetrahydro furan, 0 DEG C is cooled under stirring, is passed through dry chlorine
Change hydrogen, collects and solid is precipitated, obtain off-white powder (316mg), yield 61.4%.
Other salt are reacted in anhydrous organic solvent with different acid to be prepared.
The test of 11 platelet aggregation-against of embodiment:
The preparation of test solution: taking bisulfate clopidogrel appropriate, adds 0.5%CMC-Na solution, and 0.6mg/ is made in grinding
The suspension of ml, 2.0mg/ml to get.Same method takes compound MJ10601, appropriate MJ10602, and 0.2mg/ml, 0.6mg/ is made
The suspension of ml；Take compound MJ10604, appropriate MJ10611, be made 0.6mg/ml suspension to get.
Animal: SD rat, male, 250-270g.Totally 54, it is divided into 9 groups, every group 6.Rat is filled by the volume of 5ml/kg
Stomach gives each test liquid, and converting respectively is 1-10mg/kg for examination object dosage.Control group gives isometric 0.5%CMC-Na
Solution.
Method and result: 2 hours after gastric infusion, each rat femoral takes blood, with 3.8% liquor sodii citratis with appropriate
Ratio mixing, is centrifuged 7 minutes (1000rpm), is made platelet rich plasma (PRP)；Another whole blood is taken, with method with 3000rpm
Centrifugation 5 minutes is made platelet poor plasma (PPP).It is appropriate that PPP is added in PRP, makes final platelet concentration 5 × 109--10
×109/L.It is in right amount that inducer is added in test fluid with 5 μm of ADP (adenosine diphosphate (ADP)) test solutions, in being measured on platelet aggregation instrument
Max platelet rate in 5 minutes, and L-Arginine is calculated according to this.
L-Arginine=100% × (control group max platelet rate average value-test group animal is maximum
Platelet aggregation rate)/control group max platelet rate average value, it the results are shown in Table 1.
Inhibiting effect of the table 1 to rat platelet aggregation
* have compared with clopidogrel 3mg/kg group extremely significant sex differernce (p < 0.01)
# has significant difference (p < 0.05) compared with clopidogrel 10mg/kg group
Above-mentioned test result shows that test group curative effect of medication almost waits 6 times of dosage Clopidogrel Hydrogensulfate, and this effect
It is obviously small compared with clopidogrel should to test medication in the difference between different animals.
Pharmacokinetic in 12 body of embodiment
Studies have shown that metabolism activation generates 2- oxygroup-clopidogrel, 2- oxygroup-chlorine pyrrole lattice to clopidogrel first in vivo
Thunder, which further hydrolyzes, generates active metabolite.2- oxygroup-clopidogrel generates the rate-limiting step that reaction is metabolism, so 2-
Oxygroup-clopidogrel production quantity is to evaluate the key index of this kind of compound activity in vivo.
By investigating rat, compound MJ10601, MJ10602, MJ10604, MJ10611 are given in stomach-filling to the present inventor respectively
And after bisulfate clopidogrel, their metabolin 2- oxygroup-clopidogrel through when process, investigate after compound administration in body
It is interior to be metabolized the production quantity for generating 2- oxygroup-clopidogrel, and evaluating them.
Healthy male SD rat 15 (weight 250-270g) is divided into 5 groups, and every group 3, compound is given in stomach-filling respectively
MJ10601, MJ10602, MJ10604, MJ10611 and bisulfate clopidogrel (2mg/kg).It does not show any abnormalities, mentions after administration
Show that animal is resistant to the compound of the dosage.Plasma sample is acquired in different time points, liquid phase is used after organic solvent is handled
2- oxygroup-clopidogrel concentration in chromatography-tandem mass spectrometry measurement blood plasma, the result is shown in Figure 1.Rat clothes test compound and sulphur
After sour clopidogrel hydrogen, 2- oxygroup-clopidogrel pharmacokinetic parameter is calculated according to non-compartment model, the results are shown in Table 2.
2- oxygroup-clopidogrel medicine after test compound and bisulfate clopidogrel is given in 2 male SD rat stomach-filling of table
For kinetic parameter
Pharmacokinetic shows that pharmacological activity metabolin can be effectively converted into vivo and play by testing compound
Effect, and precursor 2- oxygroup-chlorine of generation active metabolite after MJ10601, MJ10602, MJ10604, MJ10611 is given in stomach-filling
Pyrrole Gray AUC is higher than bisulfate clopidogrel group.
Meanwhile between more each animal main pharmacokinetic parameter (such as AUC) variation, investigational agent RSD is significantly less than
Clopidogrel group.
Above studies have shown that test compound can be converted into 2- oxygroup-clopidogrel and further metabolism activation in vivo,
And the individual difference being metabolized is small compared with clopidogrel group, and the specific enzymes dependence of drug is smaller, generates clopidogrel Resistant
Possibility is smaller；In addition, since active metabolite precursor 2- oxygroup-clopidogrel amount that test compound generates in vivo exists
Etc. quality when be significantly higher than clopidogrel group, be expected to by reduce dosage, under the premise of rapid-action, curative effect is high, reduce
The adverse reaction that nonactive metabolism generates.In addition to the above compound, the 2- oxygen of preferred compound metabolism generation of the present invention
Base-clopidogrel AUC is waiting agent also greater than 2- oxygroup-clopidogrel AUC that bisulfate clopidogrel under equal dosage generates
L-Arginine is better than bisulfate clopidogrel group under the conditions of amount.
Platelet aggregation-against is tested after 13 multiple dosing of embodiment
This test gives test sample stomach-filling to normal SD rats 5 days, compares test sample different time points and lures 20 μm of olADP
Lead the inhibiting effect of platelet aggregation.
54 male SD rats are tested, are randomly divided into 3 big groups, per big group 18, give 19.65mg/kg sulfuric acid respectively
Clopidogrel hydrogen, 2mg/kg MJ10611,1.52mg/kg MJ10602, successive administration 5 days, 8~12h of fasting before last dose,
Per big 6 group of component after administration in 5th day, every group 3 only in 20 μm of 0.17h, 2h, 4h, 6h, 12h, test for 24 hours ol/L ADP inductions
Platelet aggregation rate, test method are shown in embodiment 11, calculate L-Arginine according to this.
L-Arginine=100% × (control group max platelet rate average value-test group animal is maximum
Platelet aggregation rate)/control group max platelet rate average value, it the results are shown in Table 3, Fig. 2.
Inhibition on platelet aggregation after administration in 3 male SD rat of table continuous 5 days
Test result shows that the compound of the present invention is administered with the dosage of intimate clopidogrel 1/10, the blood platelet of generation
Inhibiting effect is almost the same with clopidogrel.
Claims (6)
1. compound of formula I or its pharmaceutically acceptable acid salt,
Wherein:
R1For methoxy or ethoxy；
R2For
R4For the naphthenic base of hydrogen, the linear or branched alkyl group of 1-6 carbon or 3-6 carbon；
X is chlorine or fluorine；
N=0-6.
2. it is a kind of selected from the compound of having structure or its pharmaceutically acceptable acid salt,
3. a kind of method for being used to prepare compound as claimed in claim 1 or 2, including the following steps:
Formula II compound is reacted with formula III compound or formula IV compound, obtains compound of formula I
Wherein, the R in Formula II compound, formula III compound and formula IV compound1、R2, X such as institute in claim 1 compound of formula I
Definition, Z is leaving group.
4. a kind of pharmaceutical composition, described pharmaceutical composition includes compound of any of claims 1 or 2.
5. compound as claimed in claim 1 or 2 or pharmaceutical composition as claimed in claim 4 are in preparation for inhibiting blood
Purposes in platelet aggregation, or prevention or treatment thrombus and the drug of embolism related disease.
6. purposes as claimed in claim 5, wherein the preparation inhibits platelet aggregation, or prevention or treatment thrombus and
Embolism related disease include prevent or treatment angina pectoris, atherosclerosis disease, myocardial infarction, apoplexy, ischemic cerebral thrombosis,
Peripheral arterial disease or the postoperative thrombosis of acute coronary artery syndrome or calcification score.
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| 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 |
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